l

l' ANTICANCER RESEARCH 7: 971-990 (1987)

Pain: A Need for Paradigm Change

F. BATMANGHELIDJ

The Foundation for the Simple in Medicine, Lancaster, PA, U.S.A.

(Guest Lecture)

Abstract. From November 1979 to May 1982, I had prison has been reported (1,2). The prison diet con-
the "hoIlor" of serving time at Evin political pnson, sisted mainly of starch and pulses (such as beans,
Teheran Iran. Evin is the historical prison which has peas, lentils, a great amount of broad beans), low
set the pace of revolution in the country. At Evin it in animal protein or fat. In this report, observations on
was discovered that increased regular intake of water water induced relief of abdominal pain, which could
improved the clinical picture of peptic ulcer disease. not have been clearly associated with peptic ulcer
One of the main components of this picture was pain disease, were also recorded. Accordingly, there
of varying severity, sometimes very severe indeed. was the indication that, as well-as the symptoms
Theoretical research to find the physiological reasons and signs of the clinically diagnosed peptic ulcer
for the observed effect of water, in a condition disease under the existing, yet constant environmen-
currently classified as disease, has revealed a tal factors, being transfom1ed with increased
neurotransmitter, an osmoregulator, a water intake water intake, other types of pain also responded to
promoter status and a role for histamine. The action of "water test". A'" number of patients with hematemesis,
histamine seems to be coupled to the efficient function apart from blood transfusion, were for the first 36-48
of the cation pumps. Histamine and serotonin are in- hours given a regular drink of a strong sugar solu-
volved in the regulation of the body's water balancc. tion, followed by regular water intake (1,2,25).
Cellular "frce water" insufficiency produces a distur- In the older age group, in the same environment, the
hance of tryptophan metabolism; it is this disturbance mai·n clinical manifestation of stress was hyper-
and induced functional deficiency altering the homeos- tension of varying severity. On a few occasions, in-
tatic balance that produces pain and eventually dividuals without a history of hypertension
tissue transfomlation and/or damage. This pain is registered a systolic pressure of well over 200
being introduced as a signal system denoting free mm. mercury. One patient's systolic pressure reached
water deficiency of the cell and, therefore, it should be 300 mm. mercury. These patients were also advised to
classified as thirst pain. Histamine and the renin- increase their water intake in addition to the medication
angiotensin system also coordinate the water intake and they were receiving.
sodium balance of the body. With the induction of
The clinical observations made at Evin required
renin-angiotensin system for increase in water intake,
scientific explanation. In the laboratory we record
threshold rates for water intake and the threshold
our observations on laboratory animals; here, observa;-
rates for raising blood pressure seem close.
tions were made on human beings. If water was
Treatment of clinically diagnosed peptic ulcer dis- producing the recorded responses in conditions that are
ease with increased regular intake of water at Evin normally classified as disease, then either the clas-
sifications are wrong or the physiological effect of the
substance we recognize as water has not received due
Reprint requests to: Dr. F. Batmanghelidj, Foundation for the attention. A very extensive theoretical search has
Simple in Medicine, 111 Centerville Road, Lancaster, PA 17603, produced the following concepts. It now seems that
or P.O. Box 3270, McLean, VA. 22103-3270, U.S.A. the scope of the regulatory physiological effect. of
Key Words: Pain, thirst, peptic ulcer,histamine, serotonin, water has not received sufficient attention when
renin-angiotensin, hypertension, diabetes, cholesterol, kinins, evaluating disease processes, and that the body's
tryptophan, free water, cation pumps, neoplasia. response and reaction to simple water deficiency
This paper was presented at lh~ 1st International Workshop New Perspectives in Cancer Research, 15~18 Oclober 1987, Chalkis, Greece.
02S0-700S/R7 $2.00+ .40 971
 ANTICANCER RESEARCH 7: 971-990 (1987)
,,

has led to confused trends in medicine. In the controlling metabolism. In particular. it is

hope of generati"ng interest, the following thoughts now established that changes in the intracellular con-
on the involvement and possible role of disturbances centration of calcium regulate not only contraction in
In water metabolism responsible for disease produc~ the muscle, but conduction in nerve; coupling of
tion are presented. This course has become necessary, secretion to stimulus in cells such as platelets and
since there are no means of comparing water with mast cells, the initiation of development in fertil-
any other substance in order to discover its effect. One ized eggs and, possibly, the activation of growth in
can only rely on the body's response to regulated water normal cells_ A second Ca++ transport across the cell
supplementation, and this means simple clinical membrane, other than Mg ion dependent movement,
evaluation of the patient and his complaint before, seems to be coupled to Na+ movement; this
during and after adequate hydration: this is exactly Na+/Ca++ exchange action is dependent on the trans-
what took place at Evin. . . d b y Na +-K + ac-
mem brane N a+ grad·lent mamtame
tivated ATPasc. Current evidence suggests a
stoichiometry of 3Na+:lCa++ and that the ex.change
. THE BASIC PARAMETERS
protein functions independently of. ATP. although, in
Assuming that man is one type of space satellite the presence of ATP, the ionic affinity of the sys-
of the initial "replicators" from the "primeval tem increases. Again, according to Hesketh, the
soup" and that he has brought his salt water depend- electrogenic Na+/K+ exchange catalysed by the
ence with him, in the same way as man takes his cap- Na+-K+ ATPase, may in turn be coupled to an electrical~
sule into space with him; again assuming that subdis- 1'y silent Na +jH+ protein. In some cells this latter
ciplines of the science of biology are to be protein appears to regulate intracellular pH, whereas
viewed according to the Darwinian concept of evolution, in others Cr/I-ICOY is the predominant mechanism.
the law of the "survival of the stable" (3) would con- The mast cell secretion activation depends on free
tinue to apply to the descendants of the first cellular calcium ion in the celL It seems that, of the total cal-
crcation of the earlier creative replicators. On the basis cium content of the cells, 0.01 % exists in the free
'of this paradigm, man, the ultimate "survival ionised fonn and, of the rest, 40-60% is sequestrated in
machine" of the firsl replic3tor cell(3), would also have the mitochondria, either ionised, bound or precipitated as
to cope with the osmotic forces of the solutes In the carbonate or phosphate sait, 20% occurs 1Il the
its cell environment. We see that it has retained endoplasmic reticulum and the remainder is either ac-
the power to equilibrate effectively the osmotic cumulated in secretory granule or the nucleus, or
balance of the cells by sending sodium ions out of the bound to macromolecules. It should be borne in mind
cell and returning potassium ions inside the cells. that the activity of the plasma membrane cation pumps,
This mechanism has developed into a very complex in conjunction with the leakage across the membrane
pump system called the cation pump or sodium determines the steady-state concentration of free
potassium adenosine triphosphatase pump. Coupled ions within the cytosol (99,100). According to Edel-
to this pump action is the activation of the man and Hiatt, biosynthesis and regulation of Na+!K+
energy transfonning enzyme phosphatase. For the pump protein is thyroid dependent; this augmentation of
transport of three mol. of sodium and two mol. potas- the transport system accounts for 50-75% of the ther~
sium, one 0101. of ATP is hydrolyzed (4). The same mogenic action of the thyroid hormon.e. An 'equally
pump mechanism is developed around the important function of the Na+/K+ pump is the regula~
hydrogen ion, calcium ion and possibly the magnesium , tion and maintenance of the cell volume (100). The ex.-
ion, to activate the ATPase (4,5,6,7 ). Even the shift istence of linked passive transport of Na+/Ca++ ,
of the dominant cellular polyvalent ions, such as mag- K+/Ca++ and Na+/H+ exchange that are coupled to the
nesium and phosphorus, seem to be coupled together action of the Na+-K+ pump is also noted. There are
with the shift of potassium into the cell. According other cotransport systems for glucose and am1no
to Cronin, there is a close relationship between the acids that are coupled to Na+ ex.change because, ac-
movement of magnesium. and potassium in the cells tive transport of organic solutes by animal cells is sodium
of the body. Tn general, a change in the serum level dependent, without exception (141). Also, pH gradient
of one ion -causes the other to· deviate in the same across membranes appear to be determined by th.e . ac-
direction. Calcium ion movement, absorption and tion of the H+/Na+ transport (lDO). According' to
its bone tissue metabolism seems also, in turn, to Kaufmann and Silman (101), it seems that the ap-
be coupled to magnesium turnover (7). According to pearance of ion channels is pH regulated. In
Hesketh (99), evidence has accumulated indicating reconstituted membranes, significant opening and clos-
that cations play imponant roles within the cell in ing of ion channels takes place at pH range 2.5-3 and

972
•

Batmanghclidj: Pain: A Need (or Paradig,m Change

no appearance of channels is observed. at below pH 2 Histamine is now being recognized to be a

(101). neurotransmitter (11,12). By the ·presence of L-
Today, medical research has forced the conclusion amino acid decarboxylase and the specific L-histidine
that many disease conditions need to be controlled decarboxylase, found' in very high activity
through purposeful limitation of sodium intake, or In catecholaminergic and serotonergic neurones,
its encouraged expulsion from the body. The drugs histamine is being considered to be a neurotransmit-
most used are synthetically modified carbonic anhydrase ter, with also a specific neuronal system of its own.
inhibitors (8). particularly in the proximal part of the duodenum
(11,102,103). The basophil, Ihe mast cell, the
According to Wiggins. it seems that the
enterochromaffin-like cells, as well as the neuronal tis-
mechanism that controls, or brings about the ef-
sue that contain histamine (13), panicularly the
fective function of the said cation pumps. utilizes
neuronal tissue and the mast cell, demonstrate differing
an energy transfonning property of water, the solvent
mechanisms for the release of their amine granules
of its environment. The source of energy for cation
(111. A highly significant characteristic is the effect
transport or for ATP sylHhesis lies in increases in
of potassium ion induced depolarization; histamine
chemical potential with increasing hydration of
of the neurones and the synaptosomes is released
small calions and polyphosphate anions In the
highly structured intenacial aqueous phase of when depolarization takes place. whereas histamine
the
granules of Ihe mast cell are not released (II).
two phosphorylated intemlediates (6). Efficient I
Mast cell degranulator, compound 48/80,
operation of the (Na+-K+)-ATPase seems to require
whilst it effectively and proponionately degranu-
that the chemical potential of K+ decreases in the
highly ordered phase. The properties of the water must lates the mast cell. it has no effect on the release of
neuronal or the synaptosomal histamine (l1). ACfH
then be such Ihat lighlly hydrated solules (large
also invokes a proponionate release.. of histamine and
univalent Cal ions and anions and small non-
electrolytes) decrease in chemical potential when the serotonin from mast cells; the release process is very
phase change occurs (61." rapid and up to 90% of I-IA. and 5-1-11 of rat mast
cells is released by ACTH, and the response to ACfI-l
Water in the cells of the ~y. according to
being enhanced in the presence of Ca++ (104).
Hempling, is considered to be utilized for two dif-
Another significant phenomenon is the mooe of
ferent functions: water which is osmotically active
recovery of the amine; the synaptosomes need to be
and. by difference. that volume of cell water
hypoosmolically treated before the granules can be
which is not active osmotically. "The key points
recovered intact in the synaptic vesicles (l1,12,14)
w~re that the percentage of water in the cells
remained constant. but the fraction which was oSlnoti- The histaminergic receptors are stated to belong
cally active decreased as the cell progressed through to either HI. H2 or H3 sub-class. H I-receptor mediated
the cell cycle" (91. responses include glycogenolysis, stimulation of
cyclic GMP formation, potentiation of cyclic AMP for-
In light of the above, the efficiency of the mation, possibly linked to phosphatidylinositol
fUllctioll of the cation purnps and energy breakdown and mobilization of Ca++ from its en-
transfomlation would then be contingent upon the d~pb$mic reticulum stores involving C;:a++-calrnodulin
proportionate or quantitative presence of "free water" in complex. H2-receptors seem to be directly linked to
the area of "demand"; be this demand within the an adenylate cyclase, and their stimulation results in en-
hrain and the spinal cord, renal tissue, the hanced electrophysiologically recorded response to
gastrointestinal tract, or for mat matter any other tis- excitatory agents. HI and H2-receptors jointly seem
sue or organ of the body. to stimulate activation of protein kinase C.
In the aquatic or amphibian species, except for the resulting in phosphorylation of a protein
marine mammals such as the whale or the seal that can- regulating the 1-12-receptor-linked adenylate cyclase
nal easily utilize the sea water (10). the fluid environ- (IDS). 1-13- receptors are autoreceptors mediating inhibi·
ment would present a uniform consistency, enabling tion of histamine release from and biosynthesis in
the species concerned to adapt and maintain a histaminergic nerve terminals in the eNS. In vitro ex-
unifoml fluid intake. In terrestrial animals that have periments have shown the inhibitory action of H3-
to adapt to a non~unifoml and changing environment, receptors to be concentration dependent with a
what would happen if water intake is not suffi- maximal Inhibition of up to 60% (105). H3-recep-
ciently regular to maintain a uniform, let alone an tors arlO pr~synaptic and modulate production and
upgraded demand on the cation pumps? release of histamine as a result of feedback from

973
 ANTICANCER RESEARCH 7: 971-990 (1987)

stimulus coupled HLor Hz receptors' response (106). levels after administrJ.tion of compound 48/80, his-
When histamine is inrroduced into the lateral (amine and isoproterenol (23).
hypothalamus of rats it induces drinking even in Humes also expands on the different aspects of the
satiated animals. Gerald and Maickel have shown thirst mechanism involving the renin-angiotensin sys-
that 80 micrograms of histamine, when injected tem, first demonstrated by Fitzsimmons (108), in-
in the hypothalamus, produced a three-fold ·increase dicating that the subfornical organ is the only
in water intake even in rats that were satiated. They sug~ site for the dipsogenic receptors for angiotensin II in
gesl that central histaminergic functions may be in- the entire brain. Beta-adrenergic agents stimulate
volved in thirst-induced consumption of fluids drinking, but their action appear to be mediated Vla
(15). Leibowitz has shown that when small dosages of the renin-angiotensin system, quoting Houpt and
about 50ng. are injected into the different pans of Epstein. Hume also states that, "sint:e extracellular fluid
the hypothalamus, histamine can elicit water consump- volume is detennined by Na+ balance, the major deter·
tion in water-satiated rats; with the statement that this minants of intracellular fluid and extracellular fluid
action of histamine is a centrally and not a peripherally volume homeostasis are clearly separate: sodium
mediated phenomenon (16). According to Krall', his- balance regulates extracellular nuid volume;
tamine is also involved in the induction of drinking by water balance regulates intracellular fluid
food intake (17). In another paper, Kraly and as- volume. (24), It seems that, in any water loss, ap-
sociates demonstrate a histaminergic mechanism for proximately 66% comes from intracellular fluid
drinking elicited by insulin in the rat (18). Kraly volume. 26% from interstitial fluid volume and
funher dt::monstrate~ a preabsorptive pregastric only 8% from intravascular fluid volume (24),
vagally mediated histaminergic component of drirlk· Thus, hypovolemic shock is rare in pure or "free
ing elicited by eating in the rat (19.20); selective water" loss or deficiency (24).
gast!it: vagotomy abolishes drinking response to low On the basis of thl' above information - namely
doses of histamine in the rat. while the combination that hypul)smotic trealllll'nt stabilized the histamine
of vagotomy with angiotensin-convening enzyme granules within its veskk· .... and that the effet:l of the
inhibitor (captopril) abolishes drinking elidted by K+ by itself, enhanced hy the presence of Ca++,
higher doses of subcutaneous histamine (107). Accord- which degranulate th.: synaptosomes of its his-
ing to Goldstein and Halperin, histamine is the mast tamine; the indication that histamine and the
cell amine involved in the triggering of the drinking sympathomimetic amine isoproterenol affect plasma
response indut~ed by a hypenonic load through Na+ and K+ levels and that H2 receptor stimulation en-
the activation of an H2 receptor. TIley propose that hances elecrrophysiologically recorded responses to
the mast cell has cenain characteristics one would excitatory agents: the indication that the cation pumps
expect to see in an osmotic receptor (21). Goldstein are "driven" by water· it is proposed (25) that:
and associates. in another paper. funher demonstrate a histamine IS a neurotransmitter amlOe that
finn association of histamine and water metabolism demonstrates a mechanism of production and
of the terrestrial venebrates; the mast cell of the fish release that is extremely sensitive to the inef-
and the amphibians differ from those of higher vcr- ficient function of the cation pump; thal histamine
tebrales by being devoid of histamine; on the other is reproduced and released when there is a K+ build up
hand. in lhe reptilians, the first truly terrestrial around the site of at:tion or increased activity
vertebrates, tissue histamine is mainly stored in mast forced on the tissue. The tissue most susceptible to
cell (reported from Reite). They further report, also such fluctuation would, of necessity, be the nervous
in the reptilians, as stressed by Kaufman and system and its transmission mechanism.
Fitzsimons, that a new dimension of water balance ap- It has also been proposed that certain
pears. namely the ability to drink water when ·the need neurotransmitters, histamine in particular, dernonstratc
arises. With water deprivation and food intake, they
cenain properties that would make them candidates
demonstrate an increase in the mast cell number in the to be classified as responsible for the efficient
rat mesentery (22), operation of the cation pumps; whilst promoting
lIiroshi Izumi and associates have demonstrated water intake by the body, in the interim, they act as
that compound 48/80 and histamine stimulate an emergency substitute for water with respect to
water intake by different mechanisms, peripherally bringing about the cation pump drive (25), as well
through stimulation of the renin-angiotensin system as promoting post receptor energy release (26,105)
and t:entrally mediated by its direct action on the for this function.
brain, They also repon a change in plasma Na+ and K+ In light of' this and other' infonnation on

974
 Batmanghelidj: Pain: A Need for Paradigm Change

the apparent involvement of histamine in the water identical and thus represent EC2 granules" (Bryant
intake of the body and its functional role and associates, 3D).
as a neurotransmitter and an osmoregulator. in
According to Fernstrom, growth hormone secre-
order for cation pumps to revert to their natural mode
tion, blood pressure, pain, sle.ep and appetite seem to
of function, histamine, it seems, has become a meS 8
be strongly affected by the serotonergic
senger in the loop that promotes water intake by the
neuronal system of the brain (31). Blood pressure
"animal". It seems that the prominent serotaner-
gic neuromoclulating neuronal system is another major is reduced, the pain threshold is raised, and appetite
water intake promoting pan of the loop, According for carbohydrates is reduced, whilst protein intake is
to Holstein, the dipsogenic effect seen in the ab- not affected. According to Costa and associates,
sence of intestinal perfusion indicates that 5-HT may be the more confirmed hypothesis is that the decrease of
involved also in the regulation of drinking (27), serotonergic function in the brain or spinal cord causes
Serotonin seems [0 be involved in regulation of the an increase of sensitivity and reactivi.ty to noxious
gastrointestinal tract function: it promotes water in- stimuli, whereas an increase of serotonergic
take, inhibits acid production; inhibits acid production neurotransmission is correlated to analgesia (32).
by histamine at 33% salt water perfusion of cod Seltzer and associates, on the subject of chronic
intestine; while, with 67% salt water perfusion of the in- maxillofacial pain tolerance, Slate that manipula·
testine, the action of histamine is nOt inhibited. by tion of diet to favor tryptophan and therefore a
serotonin (27). Serotonin also promotes mucus rise in brain serotonin, results in a significant
proouction making the gastric effluence more reduction in pain intensity (33). Pollack and
viscous. Despite inhibition of acid secretion, volume associates also state, a high tryptophan diet can
outflow increases during i.m. water support, not alter chronic pain sensitivity (34). It seems that
during intestinal perfusion (27). Accordingly, 5 HT is 4
even morphia induced analgesia is produced through
the serotonergic neuronal system in t,l1e raphe nuclei of
dipsogcnic in the cod and, as with all, the ·dip-
sogenic response is suppressed by an intestinal satiety the brain, particularly raphe magnus. The activation of
mechanism, the latter probably activated by intes- this nucleus can even produce depolarization of
cutaneous afferent tenninals of mechanoceptors as well
tinal distension (27). Serotonin inh,ibits acid
as nocioceptors (35).
production in the rat stomach. As shown, 5-HT on
the serosal side caused significant inhibition of the According to Katchalski- Katzir(36), three to ten
acid secretory response to histamine (Canfield and amino acid residues are highly flexible in solutions of
Spencer 28). According to Kraly, histamine and low viscosity; as the viscosity of the medium in-
serotonin independently elicit drinking in the rat, possib- creases, confonnational changes slow down. In solu-
ly through the peripheral action of renin-angioten- tions of high viscosity, the peptide chains become
sin stimula[ion when they arc released from the mast completely frozen in their confonnation. Their data
cells (109). Laczi and associates demonstrate presence reveals that, confonnational flexibility of peptides or
of a strong stimulatory effect on the release of ar- nucleotide oligorners enables them not only to recog 8
ginine-8-vasopressin by histamine in man (115). Panula nize the biological receptors but also to fold into the
and associates (116) repon that the distribution of specific three- dimensional receptor structure. lt is
hisw.mine resembles the distribution of serotonin; that funher stated that this requirement .applies 10 en 8
histamine participates in the physiological regula- dorphins, enkephalins, ACTH and growth hor-
tion of pituitary hormones, for example, ACTH, perhaps mone. In the same vein, it is stated. that globular
by releasing vasopressin, which has corticotropin proteins "breathe", allowing oxygen consump8
releasing hOffilOne activity. Shenker and associates tion' and opening of channels to release their fanned
(119) postulate the presence of a direct central products. This same efficiency of function, as a result
stimulatory effect of serotonin on secretion of al· of conformational change acceleration, also appltes
dosterone .. to immunoglobulins and side chains to proteins, The
When a satiety mechanism is being anticipated, it implications of this aspect of hydration are vast. It
is interesting to note that, according to Christofides seems that the aromatic amino acids within proteins
and associates. water intake promotes a volume also continue to breathe or force their inherent
dependent sustained secretion of honnone motilin (29). characteristics on the constituted protein(36). Munro
Yet honnone motilin itself has been isolated in the and associates have calculated the cOllfonnational
EC cells (30); and its serotonin-like characteristics are change for tryptophan, At 5*C it has practically nO
being postulated; it is likely that the serotonin and rotational freedom. whereas at 43*C it rotates with a
motilin granules. of density 1.20 in this study are 'correlation time of 0.14 llano-seconds, indicating

975
 ANTICANCER RESEARCH 7: 971-990 (1987)

that it arises from rotation of tryptophan with the whole dent protein and enzyme function, as a result of in~
protein or a large domain of it. At 43* C. this tryp- creased microviscosity of the cytosol, further embarrass-
tophan residue acquires rotational freedom independent ing the transport systems within the cell, be it the
of the whole protein (37). This rotational property axonal transport or blood brain barrier transport sys-
of tryptophan must also apply to its loose hinding to tems. Particularly, a novel hypothesis forwarded by
albumin. Weiss and Gross, predicts (a) the force for cell
Tryptophan has to be carried throllgh the blood brain transport to be non-specific in character, (b) the
barrier (as well as through cell membrane in the transport to be micro stream born, i.e., a hydrodynamic
gastrointestinal tract or the cells dependent on its phenomenon (Ill).
metabolism) competing with the other large neutral Histamine produces a capillary dilation of the
amino acids - leucine, isoleucine, valine tyrosine blood brain barrier, an H2 receptor phenomenon
and phenylalanine - that share the same carrier (45,46). On the other hand, K+ turnover seems to
mechanism. Insul_in, secreted as a response to car- regulate capillary dilation or local Circulation in the
b<lhydrates in the diet, alters the odds in favor of tryp- brain (47,48) and presumably in capillaries elsewhere.
tophan against the competing large neutral amino The two-way transport system through the blood
acids for its transport across the blood brain barrier, brain barrier places a great demand on the efficiency
by stimulating the entry of the branched-chain amino of the local or general circulation of the brain tis-
acids into muscle ti-ssue (38,39). sue, particularly as some transport systems have
This Increase In tryptophan confomlationaI rate limitations per unit surface area of the capillary.
change, with increased enthalpy, will favor its Therefore, the efficient operation of the cation
caSler release from its albumin binding site and pump has to be in place to cope with thc demand
make a faster lock into the transporter protein possible; by increasing the microcirculation of the brain tissue
it will give it still one morc advantage at the an- in particular.
tiluminal side of the brain capillaries, where the The homlone receptor coupling depends on the three
mitochondria of the capillaries and the cation pumps dimensional fit of the homlOne into the receptor
are situated (40). This heat excitability of tryp- site. Rimon and associates state, that when the
tophan must be involved in the "shaving" mechanism
honnone or the neurotransmitter bind to the
attributed to the brain capillaries for their uptake of receptor, the catalytic unit of the cyclase is activated
tryptophan from albumin. The heat produced by the and produces cyclic AMP at the inner surface of the
cation pump has been calculated by George and membrane. Membrane fluidity affects the catalytic
associates (0), and Hempling also talks of "high unit directly, as the maximal activity of the enzyme
healS of activation" (9). There seems to be substantial increases as a function of membrane fluidity. It is
evidence that "free water", as the driving force of apparcnt that the adenosine dependent activity,
lhe cation pump and also essential in the initial the adrenaline dependent aClivity and the Naf'-
phase. of fat and protein breakdown in stimulated activity increases as a function of membrane
gluconeogenesis, IS actually bringing about energy fluidity. Ca++-ATPase, Na+-K+" ATPase and the Beta-
transformation and enthalpy of activation and, there- galactoside transport system were also found to depend
fore, is indirectly upgrading the rotational propertics on the membrane fluidity. They postulate, "Either the
of proteins and polypeptides as well as the amino receptor and the enzyme are mobile and noat in the
acids. tryptophan in particular. Accordingly, membrane, or the receptor and the enzyme are per-
it effectively becomes responsible for the efficiency of manently coupled to each other" (49). It seems that
conformational change of tryptophan and carrier or the adenylate cyclase activation is a diffusion-controlled
transporter proteins enabling them to keep up with the process. Increase in membrane fluidity also causes a
demand for their very diverse functions in' the body maximal threefold increase in the adenylate cyclase ac-
(42,43,44). In the case of axonal transport, kinesin tivity, based on the assumption that the bet-adrener-
class of transporter proteins have been identified (41, gic receptor and the cyclase are separate units and dif-
112), the assumption is that a similar mechanism and fuse freely in the membrane (50). Ross and Gilman,
type of protein transporter systems involving microtubule also quoting Livitzki and co-workers, state that in-
activated ATPase exist within other cells (113, 114, crease in the rate constant for activation of
110 ) GPP(NH)p plus epInephrine is inversely related to the
Theoretically, the need for free water in "microviscosity" of the bilayer. They are of the
gluconeogenesis, if continued, can bring about 0pIOlon that the _floating receptor model for regulation
"free water' loss" and, is thus responsible for ineffi~ of the adenylate cyclase is essentially accurate (51).

976
•

Batmanghelidj: Pain: A Need for Paradigm Change

It seems Ihat the rate of latcml diffusion of the en- ticosteroid inhibition of ad.renoconicotropin
zyme unit of the bound receptor within the bilayer rclease from anterior pituitary gland (117).
membrane of the cell determines the effectiveness of Kinins are involved in renin release from the
the honnone receptor function; and this lateral dif·
glomeruli (57). It should be noted that sodium
fusion in the bilayer membrane is inversely propor-
deprivation promotes kinin production and release
tional to the microviscosity within the bilayer. into the circulation through production of kallikreins
We have all, at one time or another, seen the Iipid- in the glands (salivary. sweat, pancreatic, kidney and
globular protein mosaic model of a cell membrane digestive tract), particularly submandibular gland
depicting a bilayer structure, with "luning fork" like (58); kinins regulate renin production, when all
projections into the bilayer from both sides. We have the time the renin-angiotensin mechanism is involved in
been told thai the external surfaces are hydrophilic and thirst production and water regulation; sodium
the projections into the bilayer are hydrophobic. Some seems 10 be involved in cell pH regulation through the
may wrongly assume that the "hydrophobic" property action of Na+·H+ pump (59,60.99), when pH
means that water does not get into the bilayer changes can convert prekallikrein to kallikrdn,
mcmbrane. Rand and Parsegian have shown that with the resultant fom1ation of bradykinin or kallidin
water scparates the bilayer structure of lipids to from kininogens, kinins, capable of causing pain (61), as
either a fixed distance of 20-30 A in Ihe case of well as the other functions they perform.
an electrically neutral bilayer or to indefinitely large
The serotonergic system in the brain and the
separation of up to 100 A in the case of a charged periphery is another such complex network of a
bilayer(52). A lateral diffusion pressure is also
neuronal system that seems to be affected when there is
developed with the introduction of water in the a deficiency of hydration. The serotonergic system in
bilayer. The above infonnation pennits rhe thought the brain has three types of receprors: S I, 52 and 53.
that these hydrophobic "Iuning-fork-Iike" projections
The receptor classified as 52 is an autoreceptor; it is
may act as mixers or stirrers in the bilayer presynaptic and mediates collateral inhibition, or
membrane, by being responsible for a build-up of the it may have a direct inhibitory action. The S3 recep~
lateral" diffusion pressure between the fork-like tor is found in many pariS of the brain: it too has an in·
projections: they may bring about a more efficient hibilOry function. 51 receptor is found in postsynaptic
"honnone-receplOr-enzyme" action within the localions. its function is neuromodulatory (62). Sub-
bilayer membrane (for the receptor Iypes that stimu·
types D and M are reported in the muscle and the
lale function within the bilayer), the microviscosilY
skin , with type M being funher divided into three
of (he space having also been adjusted. when free
subtypes, one of which is involved with pain registra-
watcr diffuses through the phospholipid rnembrane.
tion (63). Skin seratonergic receptors are also involved
l3ecause the inherem propeny of the cell membrane
in the rhcmlOregulation of the body. Histamine
;s lO be a barrier for ions and most polar molecules,
receptors will similarly be· influenced by the ef-
whilst permiuing water through the lipid membrane
ficiency of the feedback mechanism, particularly since
by the process of diffusion. The pem1Cability
H3 receptors have a major role in HI-H2 inhibition.
coefficicm (em/sec) for water is 10- 3 and for sodium
and potassium ii is 10. 12 (53). The diffusion ratc In the discipline of gastroenterology, thc
through the membrane is ultimately dependent on Ihe epigastric pain not associated with the presence of
composition of the membrane. cholesterol COnlems an ulcer crater or with a definable pathology, such as
of the membrane being the detennining factor in the cholecystitis or pancreatitis is not considered imponant,
rigidity, and thus in the comparative impermeability in most cases, it also shows equal response to an-
of the mcmbrane (53,54,55). These conccpts indio tacids, cimetidine or placebo" (64). When, with' a
Gue the imponance of water in fine regularion of similar pain, a macroscopic ulcer crater is seen. the
the interlocking hormones, neurotransmitters and treatment of choice then becomes H2 receptor blocking
ncuTOmodulr\lors' action in the body. This concept may agents. Between that initial nondescript pain and
seem important to the function of neuromodulators or the final visual stage, the "same characteristic
neuroendocrine systems that regulate themselves on pain". with some local mucosal change. is classified
the basis of a feedback mechanisms. This could also in- as gastritis. ducx:ienitis, esophagitis and so on. At
clude the short loop negative feedback that seems to times, an aUloimmune state is postulated. Is separation of
exisl between renin production and angiotensin II these stages as different conditions accurate? If the
inhibition of renin production (56), and also the fast and ultimate stage is to be treated with an H2 blocking
delayed feedback mechanisms that regulate cor- agenr, then we are interfering with a neuTotransmis·

977
 ANTICANCER RESEARCH 7: 971-990 (1987)

sian mechanism that is involved in the water intake of (70). If the level' for free tryptophan reaches to
the body, and possibly substituting for the function more than twenty percent, the liver will metabolize
of water for the cation pump drive, until the deficien- the excess(71) by induction of the enzyme tryp-
cy is replenished. It seems reasonable to assume that in tophan oxygenase; also as a result of increased free tryp-
such circumstances the interlocking control tophan in circulation, the enterochromaffin cells in-
mechanism may possibly not be operative until full crease serotonin production which will be taken up
hydration takes place. The parietal cell uses up vast by the platelets (133) and mast cells (22); whereas in
quantities of water; full function of the parietal tissues other than the liver, tryptophan metabolism oc-
cell requires transport of large volumes of water from curs through induction of the enzyme indolamine
the circulation (13). It requires water in order to operate dioxygenase and production of superoxides
the H+-K+ ATPase pump (6). When this nonnal physiol- (72,73). It seems that, through induction by cortisone,
ogy is not efficient. histamine takes over, since the the liver enzymes, tyrosine aminotransferase
capillary circulation of the stomach has H2 receptors as well as tryptophan oxygenase are activated,
(65). Histamine will continue to maintain the in- with the possibility of eventual depletion of the
tegrity of the local circulation, at the same time produc- body's pool of tyrosine and tryptophan (Bender 72).
ing a central pain alann; low pH conversion of Depending on the ratio of the intake (animal protein,
kininogens to kinins may be the pain inducing meat, has very low tryptophan content compared to its
mechanism (61). transport competitors, 31), to the over metabo-
According to my clinical observations and the exposed lization by the liver (71,72), causing an induced
theoretical reasons, the abdominal pain, when other tryptophan insufficiency (74), and altered route of
local pathology suth as cholecystitis or other definable metabolism, signs as well as symptoms will then be
conditions are not suspected, should be considered to produced. It is important to note that when a com~
be a "thirst pain"; in fact, a glass of water can serve bination of protein and fa[ is exposed to oxygen,
as a diagnostic tool (1,2,25). This initial pain is the im- oxidation of fatty acids and the release of free radi-
portant signal representing the malfunction of a cals results in some essential amlllo acid's
water regulated system, because, when insufficient deterioration, among them tryptophan, lysine
hydration that has caused pain continues, a and methionine; lysine loss can be high and
physiological state inducive to tissue transformation methionine loss can be total (74). This information
and/or tissue damage is then created. Depending on is particularly important Since lysine, III conJunc-
the duration of the body protein and enzymes' lower tion with tryptophan, acts as an enzyme system for
rate of production and functional down- regulation, recognition and repair of damaged DNA (75). Meat,
which could include the class of body proteins when exposed for marketing, could be a candidate for
known as "receptors" be they interferon receptors, this deterioration.
cholesterol receptors, insulin receptors, sex steroid Under such circumstances, tissue damage or its
receptors, or any' other class of receptors ~ the dif- transformation will involve more than just the
ferent stages of disease conditions will be seen, gastrointestinal tract and its gastric or duooenal dis-
This question about the rationale of separation of pain orders.
and the different stages of' tissue damage in peptic TryplOphan, is possibly involved in the antiviral tis-
ulcer disease has been voiced by Spiro (66). sue defense mechanisms by production of super-
t'nfortunately, in "stress", assumed to be induced oxide of anion and hydrogen peroxide. It seems
hy cellular free water depletion, the amino acid that interferon stimulates the synthesis of prostaglandins
tryptophan - whic;h determines the level of activity of in the cells, which in turn bring about induction of
the serotonergic neuronal system and possibly other indoleamine dioxygenase (73), It is important to con~
indoleaminergic 'activity, that among other functions sider this link in the chain when conditions of ap-
rai,e or shift the pain threshold (31,35), as well as parent deterioration in the body's immune system
regulating all aspects of the pituitary~adrenal functions are being investigated, even if we are searching for
(67.6R,69) - will be one of the more important ele- a viral depressant of the immune sy,'item because, in cer-
ments that will become quantitatively depleted as a tain circumstances, a plasma borne tissue~CRF, with ex-
result of its over metabolism by the liver, 'and the tryp- treme potency and prolonged course of action, "intestinal
lI"lphan that remains is rendered less effective by stress" induced, can be transferable through blood or plas-
the decrease in its rotational properties. One of ma (124,128,142).
the events, that seems to take place is a change in the Tryptophan IS involved in protein synthesis and
ratio of free to bound tryptophan in circulation in tissue repair, especially in high turnover tissues

978
•

Batmanghelidj: Pain: A Need for Paradigm Change

such as the stomach and the intestines, when secreting property (118), It is understandable, since
protein synthesis and the regeneration of cells need the blood circulation operates within a closed system,
tryptophan in particular, According to Majumdar, that any volume change has to be compensated
force fceding of L-tryptophan stimulates amino for immediately, otherwise a "gas lock" could
;icid incorporation into albumin, fibrinogen, develop, causing a malfunction of the system. This
transferrin and ferritin; by its· effect on protein synthesis compensation seems to be secured primarily by "bor-
in the gastric mucosa, there is indication that rowing" water from the other two compartments to
dietary tryptophan plays a significant role In the extent of 92% (24), while the other 8% is made up
maintaining the stntctural and functional properties by closing the system proportionately, If through in-
of the gastric mucosa (76) and, undoubtedly, other tis- adequate intake of water, the body continues to run
sues of the body. on a deficit (82,83,84), then, by manipulation of
Even at the level of damaged DNA, it is postulated· the osmotic forces through saIl retention (or glucose
that tryptophan, ~n conjunction with lysine (and threshold manipulation and possibly retention of uric
glycine), acts as an enzyme system for the recogni- acid), it will continue to borrow water from the
tion of a damaged site and for its repair(75). Also, ac- other compartments in order to maintain a compara-
cording to Seymour Zigman, among the tive integrity of its blood circulation and, therefore,
photooxidation by-products of tryptophan, the brain cell volume. It is interesting to note that, with
sub-groups PPI and PT2 demonstrate cell division salt deprivation, there is a higher turnover of
antagonism, and also act as enzyme and protein in- glandular kallikrein in the glands of the body, apparently
hibitors, since they mimic the action of organic as an agent for induction of vasodilation to maintain
peroxides. PT2 appears to be a better macromolecule circulation (58). This sodium retention could have
synthesis inhibitor than other tryptophan oxidation a much more important functional role than merely
products (77). Whether photooxidised or indoleamine being needed for maintaining the extracellular' fluid
dioxygenase induced, it appears that by-products of volumes. Since membranes are functionally asym-
tryptophan metabolism have marked influence on the metric, particularly with respect to the ionic pumps
defense and regulation of cell function when the func- (53), and the primer of these pumps is a build up of
tion of lhe cation pump is adequately maintained. the particular ion on the "intake side" of the pump,
and since the function of all cells has an inherent
It is worthy of note that, even when H2 blocking property of continuously buffering its energy charge
agents arc used to "repair the ulcer", the repair time as well as its pH change (53), this sodium retention
depends on a natural healing rate; according to may be a very delicate balancing component of the
Gregory, even with the "tissue" covering the ulcer cell pH buffering system in some cells (99). Selvaggio
crater, morphologically the site of damage is not con- and associates, expanding on the work of Rindler
sidered normal or fully repaired (78). It seems that and associates, have demonstrated the existence of a
the 1I2 blocking agents, among them the tricyclic an- Na+-H+ pump (59). Livne and associates also propose
tidepressant dnlgs being very potent Hi blocking Na+ to be involved in the pH buffering system of the
agents (79), influence the serotonergic neuronal system body (60). It is assumed that this pump also operates
(KO). In view of the fact that the cerebral capillary in a similar way to the other cation pumps, namely that
system has H2 receptors for dilation and increased cir- "free water" is responsible for driving it. According
culation, the question arises: when these drugs are to Cooke, sodium uptake by the enterocytes may be af-
used, is the brain tissue being forced into a functional fected by the level of tryptophan made available
hypoxic down-regulation ,to heal the ulcer, or to treat to the tissue (rabbit jejunum); "tryptophan increases
depression? electrogenic sodium absorption, followed by inhibi-
I-laving discovered that the renin-angiotensin sys- tion of the active sodium absorption." This regulation
tem IS histamine induced (23), and being armed between inhibition and stimulation of absorption
also with the knowledge that the renin-angiotensin depends on the quantity of the amino acid made avail-
system is the operative peripheral drive for water in- able to the tissue (85), when serotonergic neuronal
take by the body (23,24), it becomes equally very im- system directly and indirectly, through aldosterone
portant to know that the threshold rates for water in- secretion, also promotes sodium retention (119). In
take and the threshold rates for raising the blood pres- light of the above, malregulation of the cell pII-
sure seem to be very close (81). In the dog and rat may be the cause of pain in tissues other than those
these rates are antidiuretic and antinatriuretic (81), pos- of the gastrointestinal tract, in the same way as
sibly because angiotensin III, a septapeptide metabo- was proposed for the abdominal pain, particularly
lite of angiotensin II, has a direct aldosterone as, according to Goldstein and associates,

979
 ANTICANCER RESEARCH 7: 971-990 (1%7)

generation of endogenous kininogen spliuing en~ wards the brain capillaries grJdually lose their
zyme(s) responsible for bradykinin production is/are in- responsiveness to breathing 100% oxygen, and in-
accessible to exogenous or circulating substrates (121). creased CO2 tension (86). We must assume that if
It is interesting to note that proc·aryotes regulate the receptors involved in evaluation and com-
the fluidity of their membrane by varying the number pensatory adaptation to fluctuations of
of double bonds and the length of their fatty acid oxygen and carbondioxide tension lose their edge,
chain to alter the fluidity of their membrane; as a from the age of twenty onwards. then the same prob-
process of adaptation to environmental change, ability applies to the ability to evaluate the water
they take this course in order to survive. This has content of the body to the point of inducing thirst
been shown in E.coli (53). In eucaryores, cholesterol mechanism as a finely adjusting sensation, in order to
IS Lhe imponant regulator of membrane fluidity. keep protein and enzyme function at the optimum for
Thus cholesterol moderates the Ouidity of the that body (25). Bruce and associates have also
membrane (53). This phenomenon seems to demonstrated a definite predisposition 1O a lasting

demonstrate itself In the tracheal epithelial cell api- change in the body water composition with age. The
cal membrane. According to Wonnan and associates, ratio of extracellular water content to intracellular
increases in fluidity correlate with increases in water water content change from an approximate 0.8 to al-
pemleability of these membranes. At a tran- most 1.1 between the ages of 20 to 70 - a very drastic
sition temperature of between 28-26*C, cholesterol sig4 change in composition (87). We are more and more
nificantly decreases water permeability above coming to realize that older people are chronically
phase transition temperature of planar lipid bilayer, and dehydrated, losing the capacity 10 rehydrate their
increases it below the transition temperature body, even though obviously dehydrated (82,83,84).
(54). If water pcmleability through 'he cell with a predisposition to hypothennia, yet we do not
mcmbrnne commands such fine regulation as make a strong effort to compensate Jor this problem
even to dictate a membrane's structural change, and if over a longer period of time before their "ailment" is
in chronic water loss the cel1ular ·...;"ater content be~ treated, sometimes vel)' drastically, as for example with
comes depleted, and if each cell ·in the' body, to a vascular s.urgery for intermittent claudication, or allow
lesser or greater extent, has an individual power of a:nginal pain to proceed to its logical conclusion.
adaptation very much like that of E. coli, then should We must reevaluate the concept of dry mouth as a
we not expect a "cholesterol" adaptation sale sign of thirst, first proposed by Haller and ar-
phenomenon? If these adapting cells are exposed to dently supponed by Cannon; we must accept and ex-
(he osmotic forces of the blcxxi, drawing their water plore Schiff's original evaluation of thirst as a
directly, would there not be a logical regional general sensation of the body (108).
defensive build up of cholesterol within the cell It is taken for granted that, coupled ·with the process
mcmnr:tne, to bring about a foml of protective adapta~ of aging, the body gradually loses its reserve capacity;
tion, in order to survive?· protein and enzyme functions are trimmed to the
basic day-to-day requirement. yet, at any age a fonn
DISCUSSION of homeostatic balance is established for that body
and its nonn of activity. To optimize the protein
Up (0 now, we in the medical profes.sion have and enzyme functions for this period of life, maxi~
taken lhe water consumption of the body for graAted. mum activity of the cation pumps and the energy trans-
\Ve have considered it to be a self- regulating fonning enzymes should be assured. through in-
me.ch'l1lism that will take care of itself. We have creased hydration. It is also in this group of people
relied on the sensauon of thirst as an everlasting that pain, as a signal system of the inefficient opera-
quality of the body. It is true that whenever we treat tion of the cation pumps, develops significance and im~
a sick patient in hospital, we fuss about· water in- ponance.
take and the electrolytes, but by and large our other At this point, Medawar's opinion finds SIg-
patients are not controlled for their fluid intake (not nificance. Dawkins (3) considers that the body is
drying agents, such as coffee tea and alcohol, the just a survival machine for the genes we have in-
latter through inhibiting the secretion of an- herited. He is of the opinion that every function of the
. tidiuretic hormone 140,24). We must assume that all body is genetically detennined, even predeter-
sensations of the body lose their edge with the passage mined. He expands on Medawar's opinion that
of time, including the thirst sensation. Sliding there are late acting semi-lethal and lethal genes. It
Meyer has shown that from the age of ~wenty on- is said that senile decay is the result of the activity of

980
 J3atmanghelidj: Pain: A Need for Paradigm Change

these genes, when the "good" genes have given way. It within (135). Marx considers the two steps of
is being said that there are certain "cues" which "turn immortalization of the tumor cell and its tumor fonna-
on the late-acting lethal genes. Let us expand on this tion are separate steps involving different genetic
subject. Crowther, in his research on the effect of drives or possibly removal of the inhibitory
cations on the rheological properties of purified phenomena in which the role of interferon is stressed
mucus glycoprotein gels, discovered that Na+ (136). Weinberg is of the opinion that the environment
reduced the gel elasticity, whilst the divalent cations of the cell is of utmost importance in responsiveness to
gener,dly increased the elasticity of mucus. He uses viral oncogenes and its spread (137).
the interesting concept of "charge shielding" by the The relationship of these phenomena in conjunction
monovalent cations (88). Thomas Record has with changes in the microviscosity of the body and
proposed the existence of a specific coptrol the inefficient function of the cation pumps should be
mechanism involving the direct effect of change addressed. Because, if histamine IS one of the sen-
in ion concentration on the interaction of proteins. and sor regulators of water balance in the body, it also
nucleic acids and on the stability of nucleoprotein COI11- acts as vasopressin secretion stimulant (l15).
plex (89). We understand that the cytoplasm of Vasopressin In turn acts as ACTH secretion
the cell is negatively charged. We understand that when stimulant, since it is being proposed that cor-
the three Na+ are exchanged for two K+, after the ini- ticotropin releasing factor may be modulated vasopres-
tial elcctrogenically silent exchange of the H+ for sin (122); therefore, as a potential CRF secretion
Na+, the cation pumps are maintaining a pH and stimulant, histamine is involved in beta endorphin
ionic eLjuilibriuTll in this direction, particularly as the and ACTH secretion, mediating the integration of
shift of the other polyvalent ions into the cell is in body's response to stress (123). ACfH itself also
turn coupled to the shift of K+. In this way the pos- acts as secretion stimulant for mast cell release of
sihility of the damaging effect of excess hydrogen ion serotonin and histamine (104).
and the effect of "charge shielding" of the
monovalent cation on the glycoprotein struc- According to Goldstein and associates, there
ture of DNA is decreased. Is it possible that the inef- is also a direct thymus adrenal connection (I25), with
ficient operation of the cation pumps could predispose the result that corticosteroids cause a thymic involu-
to "jumping genes" and creation of "selfish DNA'!" Are tion, T lymphocyte mitotic suppression, and inhibition
"selfish DNAs" the "cues" for the action of the of human leukocyte's phagocytic activity. Lower
"semi-lethal" or the "lethal" genes? If so, then, by the concentration of glucocorticoids would rave the
same token it is possible that the maintained ac- reverse effect: enhanced thymocyte differentiation
tivity of tryptophan (through adequate balance in lhe and increased antibody fonnation in vitro. Thymus is
cdl free water content and a balanced diet with also being implicated in production and release of tis-
least deterioration of the essential amino acids) could sue-CRF (125,124) with a delayed but prolonged dura-
be more effective in the recognition and repair of the tion of activity which is stress induced (128). Makman
damaged DNA (75). According to Levinson, and associates have shown, in vitro, an inhibitory ef-
"there IS compelling evidence that human cancer fecl of cortisol on amino acid transport and nucleoside
develops as a consequence of genetic damage (90). transport and/or phosphorylation in lhe thynrocyte,
Dawkins ventures an opinion that viruses are genes through induction of synthesis of proteins with in-
lhal have broken loose (p.196,3). Green and Wyke hibitory influence; they also report on Hechter and
indicate that recent advances in molecular biology have associates' observation that there is a marked decrease
shown that viral oncogenes of rapidly transfom1- in K+/Na+ ratio in thymus of adrenalectomised rats
ing retroviruses were shown to be derived from and after repeated injection of cortisol (134). Makara also
represented a subset of host's cellular genes (cel- stipu!ates th~ role of vasopressin as a CRF in stref;S
lular or proto-oncogenes) present in normal cell DNA. induce,d piruitary-adrenal system stimulation. There
Proto-oncogenes are now believed to playa vital role in is a weaker action of serotonin and angiotensin
cellular proliferation and/or differentiation.' Cellular on ACn'! release (124,126), from multiple sites
homeostasis exercises a regulatory action on the activity of action (127). The role of serotonergic
of these proto-oncogenes (138). Bishop proposes neuromodulation in the brain has to be separated
that retrovirus oncogenes characterized as of exttrnal from serotonin's short tenn peripheral action when
viral origin are possibly from ·the· host's celiulai"lQC\ and evaluating isolated experimental results.
not of external viral origin; this discovery is con- At this point, reference to some other aspects
sidered to be a very fortunate happenstance~ trtdicating of tryptophan metabolism becomes important.
that in carcinogenesis the. enem?: ~o~.ld be from According to Gerald Huether, serotonin is in-

981
 ANTICANCER RESEARCH 7: 971-990 (1987)

valved in the regulation of cell division and the tissue damage or its transformation phase is
(cleavage, separation of mitotic centres), intracellular the result of not having recognized the meaning of that
flow, cell shape, morphogenetic and .pulsatory move- pain signal, which now means both water deficiency and
ments, primary invagination, neurulation; it is also inadequacy and disturbance of tryptophan metabo-
involved in the control of transcription and transla- lism (25).. Depending on the age of the person, the
tion of genetic information. Cell migration and synap- pain signal may well be an indication of a
togenesis in the developing brain are controlled by predisposition to the precipitation of a variety of disor-
serotonin. As for another tryptophan dependent ders that will be determined by the role of tryplOphan
product, tryptamine is an 'phylogenetically old in the body. This pain may even herald a continued
modulator of intracellular communication, affect- predisposition to disorders that may affect that
ing the metabolic state and the function of develop- person's offspring (69). This all encompassing role
ing cell. He is of the opinion that. in nature, of tryptophan and its by-products of metabolism must be
an increased availability of tryptophan 10 individuals the delennining factor in the genetic association
of a cenain population would never occur, since between a large variety of conditions and peptic
several substrates and cofactors are involved. H~ fur- ulcer disease that Jerome ROller lists (91). He is of
ther Slates that altered nutritional . supply of tryp- Ihe opinion Ihat peptic ulcer is not a single disorder,
tophan during the development of an individual may but a host of disorders that share a common clinical
cause vanous metaoolic alterations. Such responses finding: a hole 111 the lining of the gastrointestinal
seem to last and to become continuously tract: similarly, heterogeneity IS being recognised in
modified through several generations until a new gastric cancer.
steady state is finally reached (69). The significance of the role of serotonin and his-
tamine in the regulation of body physiology,
According to Kandel and associates, evaluating the
through calcium turnover in the cell, is of paramount
effect of serotonin on modulation of Ca++ current
importance; since histamine through the combination of
during behavioral arousal, a qepolarizing command
H], H2 receptors activates protein kinase C, which
pulse produces an inward current due to Na+ ,as well
catalyzl::s calmodulin-dependent phosphorylalion of a
as Ca++ followed by an outward current due to
class of protein that has bel::n identified for sarcoplasmic
K+, \Vith repeated commands, the peak inward cur-
reticulum of the cardiac muscle as phospholamban,
rent hecomes less inward. Adding serotonin again podudng :.t three-fold increase in Ca++ uptake and Ca++-
now causes the trdnsient current to become more ATPase activity, a potential Ca++ translocator (5), and
inward. reduces leakage, and shifts the holding current
lhus primes lhe cell growth process thal is calcium
inward. Identical effects are seen in the absence of the
dependent and since through the manipularion of
Na+ current (93). This manipulation of the cal-
1'\ a+/K+ pump, which is a voltage inducing pump,
dum current by serotonin must be considered (Q be its
generates ionic current and voltage gradient that. ac-
most imponant role in the physiology of the body.
cording Jaffe (129), is essential for detemlination of
h must be this effect that inhibits the histamine ac-
cell growlh, histamine may be considered to be a
tion In the experiment conducted by Canfield and
direct primer of growth within the cells. This idea
Spencer. when serotonin from serosal point of contact
could be funher supponcd by the observation of
inhibited the acid secretory effect of histamine, also
Bender, who considers histidine one of the essential
showing a threshold phenomenon (28).
amino acids for growth in children (72), hy the way
At.x;ording to Lippman there is an association be- cimetidine reverses tumor growth enhancement of plas~
tween psychosocial factors and the hormonal regula- rnacytoma tumors in mice (130), and by the fact [hat
tion of tumor growth. He is of the opinion that emotion- mast cells multiply with each degranulation
al factors can profoundly regulate hypothalamico- of histamine. The presence of L-histidine
piHiitary honnones; neuroendocrine honnones- in tum, decarboxylase, an indicator of histamine activity
directly or indirectly, regulate neoplastic cell according to Beaven (13). is found in many tumour tis-
growth or alter concenrration or activation of other sues, including mastocytomas, gastric carcinoid
hormones that affect cancer cells (131). tumours, transplantable hepatomas and mast cell as-
If, according to Dawkins, all actions of the body cites tumour; in the rat tumour tissue, the enzyme is
are "genetically" determined, then, philosophically found to reach very high levels (13). The action of
speaking, certain types of pain could be the "genes' serotonin on stabilization of the calcium current, must
cry" in "anticipation" of damage. particularly the recur- be the balancing factor in this relationship.
ring dyspeptic pain of peptic ulcer disease (regard- This physiological stale mUSl be considered a logical
less of the presence of a macroscopic ulcer cmter); adaptation to life on land, when 'the Ixxty is at-

982
 Batmanghelidj: Pain: A Need for Paradigm Change

tempting gradually to become independent of con· taminergic or melatonergic neurones. The role of
stant need for water, very muc~ like the reptilians; these neurotransmitters in the maintenance of
except that emotional, socio-economicaJ, and en- homeostasis in the b<xIy 1S complex., and needs
vironmental factors disrupt integration of adapta- more attention. There seems to be a definite
tion to the needs of the total body, where upon the relationship between the water metabolism of the
natural drive for survival only manages to "liberate" body and seroronergic neuronal function. If the
some pans of the anatomy from environmental regulatory role of the brain cells determines the
slrains. The same will to survive must be the state of the body physiology, then the role of
natural determining factor in remissions attributed to serotonin in the maintenance of that regulation is
the "fighting spirit", a natural component of "fight important. If, according to Hume, in pure water
or night", when the body as a whole decides to'sur- loss, the brain cells adapt by increasing intracel-
vive. lular osmolality. sugar, salt and "idiogenic solutes" are
It seems that, in stressful sedentary occupations, when involved (24); if according to Fernstrom, 5HT syn·
the activity of large muscle mass in the body does Ihesis is reduced in the diabetic brain, secondary to
nOI bring abour the dominance of fat metabOlism btain tryptophan levels (96); if according to Ikeda
through activation of the hormone sensitive lipase, and associate (97) and Hattori (98), xanthurenic acid
which seems to be time dependent (92), resulting in can render insulin physiologically less effective,
a net gi.lin of water for the cells, and protein break- and we know that xanthurenic acid is a liver metabo~
down continues to be a major component of lite of tryptophan, what could be the role of disturbed
gluconeogenesis; when muscle metabolism does waler regulation in pr<xiuction of diabetes? Could
nOl adequately utilize the branched-chain amInO diabetes be a crisis state to brain cell volume reduc~
acids, leucine isoleucine and valine (72), Ihe blood lion? Could nature be involved in resuscitating the
brain barrier competilors to tryplOphan, the actual brain in the same way as we use deX'trose saline? Ob~
phenomenon of tissue damage and or tissue viously, there is no "insulin barrier" to enrry of
tri.lnsfonnation associated with slress will develop. A glucose across the blood brain barrier, whereas, ac-
physiological translation of "fight or flight." tive transpon of glucose across other cell membranes is
dependent 011 the Na+-transpon protein-glucose ternary
complex formation with a stoichiometry of 1 Na: 1
Pre-Conclusion glucose (141). Thus: thirst associated with a higher
In any future drug trials, the curative effect of than nonnal blood glucose level may be a primary sig·
waler has to be separated from the effect of the nal for water deficiency.
chemical composition under investigation. This We often see double blind randomised trials produce
can be done by hydrating the patient well for' some almost as good a result for placebo response as that
time before and during the time that the trial is carried produced by the medication under investigation
out. At the same time the idiosyncrasies of the metabo- (120). Often the placebo response is discarded as too
lism of tryptophan should also be taken into account. h good to be accurate. It must now be recognised thaI
seems that tryptophan loosely binds to albumin and water taken with the pill, with all its regulatory
thaI free fatty acids compete for that binding sire; properties, is responsible for the placebo . effeci
not all animal protein has a high tryptophan content, (2,25). Extensive observations need {<f'>be made on
whilst more than onc fifth of the weighl of mOSI meat lhe response of raised systemic or so-called essential
consists of fat. The presence of unsaturated farry hypertension to increased hydration (25), par·
acids, when also exposed to oxygen, could poten- ticularly as water by itself is the best natural diuretic
tially bring about the deterioration of some of the es- (8). It seems that we must rethink our approach to the
senti;1I amino acids even before intake of food treatment of hypertensives by administration of chemi-
(74). It is interesting to note that a high content of cal diuretics and sodium reduced diets. We may have
pulsl:s III the diet could provide a reasonably LO allow adequate water intake to adjust the cell
balanced protein intake, particularly of the amino volUlne, as well as the ex.tracellular fluid volume. as a
acid tryptophar.; up to 90% of the "recommended" reo preventive measure before tissue damage lakes
quirement of the body can be supplied from this pla<..ce; because the natural drive of renin-angiotensin is
source (74). Attention to the tryptophan content directed towards increased water intake (81), and
of food is most important. For, oul of the total intake, its hypertensive property is a compensatory
only a small portion crosses the blood brain barrier, phenomenon. The dietary approach should be
getting converted to the indispensable neurotransmitters directed towards an adequate supply of the essential
as soon as it reaches the serotonergic, tryp- amino acids because histidine turnover may cause a

983
 ANTICANCER RESEARCH 7: 971-990 (1987)

body depletion of this essential amino acid. Par- the significance of the crisis produced is the indication
ticularly, as Holcslaw and associates have that an occasion for retooling has arrived. Crisis
demonstrated a reduced histamine level in the wall loosens the rules of nannal puzzle solving. When
of the aona of the spontaneously hypenensive rats, al- the anomaly appears to be more than just another puz-
though possessing an increased histidine uptake zle of nonnal science, the transition to crisis and
capability (132). I have seen very satisfactory results to exrmordinary science has begun. Even fanner
from treatment of essential hypertension with standard solutions of solved problems can be called
increased water intake (25). It seems to me that into question. According to Lakatos and Musgrave, no
what we are seeing in hypertension is the body's ordinary sense of the tenn "interpretation" can fit the
response to extracellular water loss through the nashes of "intuition" or "imaginative posits"
early loss of thirst sensation, and we are treating the through which a new paradigm is often born (95). The
hypertensive threshold and not the basic accepted paradigm on the metabolislll of water IS
physiological drive (25), for water, of all things, the based on the infallibility of the physico-chemical
most essential component of the body. properties of ions within the cells and assumes that it
When mast cells degranulate and serotonin and is this property which determines water regulation and
histamine are released into the microcirculation, the thirst mechanism. This view. whilst sound, does
serotonin. as well as histamine and bradykinin, has [he not take into account the "metering system." If
propeny of compromising and breaking the wall and the serotonergic neuronal system is considered to
producing gaps in the wall of the capillary (44). This be the regulator of the homeostatic bal:tnce in the
regional effect of histamine and serotonin may be a body - and according to Kandel and others it is even
precipitating cause of local ulceration of the duodenal involved in the regulation of the ionic channels within
region that seems to have histaminergic nerve supply the nerve cells - then what happens to this halance
(I (3). When the compromise of the capillary wall oc- when lhe tryptophan reserves of the body become
curs 10 the blood brain bamer region, the result3JH depleted and its metabolism disturbed? If thirst sen-
local inflamm.ltion and plaque formation call be ac- sation is gradually deteriorating. what are the conse-
cepted as a logical conclusion. TIle consequences of quences of under hydration and from what age do they
thi:- phenomenon could become of catastrophic begin? The above theoretical discussion, hased
dimension if a potentiaJly higher aluminium con- on human observations. in a constantly stressful
centration in blood is brought about with increased ant- "laboratory" condition, where. the levd of stress and
acid intake (139) to relieve a thirst pain. diet of pulse and starch were. the constant factors. is in-
tended to expose the important lack. of sllffi~ient
Pain associated with decreased capillary circula~
knowledge of water metabolism in the body; it is
tion. such as anginal pain and pam of inter-
also intended to 4uestion some of the basic under-
miltelll claudication. needs to be investigated with
standings of certain "disease" conditions.
increased hydration as a fonn of treatment prior to
drug lise (25).
In order that acwal. or perceived, mental or emo~ CONCLUSION
lional 'Il'iivity or emotional experiences should not
produ<.:c adverse symptomatic or physiological response \Vhen severe atxiominal pain, often associated
in the body. precaution with increased hydration of wilh peptic ulcer disease," is relieved with water
the hotly should be taken. so that the blood brain (and this phenomenon reveals a basic concept of
harrier capillaries are optimally hydrated. which a very brief form has been presenled above).
it seems that the time has come to reassess our ap-
Reassessment of the drug dependence of patients
proach to treatment 111 medicine. We must now
under medication is indicated after increased hydra-
recognize a pain signal to cellular free water deficien-
tion.
cy of the body and also recognize the impending conse-
Low back pain need be treated with increased water quences of its misinterpretation. We must assume that
intake. as the efficiency of function of the discs also thirst sensation is no longer a reliable mechanism
depends on their hydrolic properly (25,94). for the regulation of the delicate balance of cellular
According to Thomas Kuhn, quoted by Crue and hydration. We must enl:oumge people to regulate
ass(,)(:iates under the subject of "continuing crisis in water intake by establishing the habit of drinking
pain research" (95), when anomalies in the. observa- water. It seems that water intake before meals
tions of science proliferate and cannot be recon- should be encouraged to prevent hemocon-
cikd within the rules, or the basic paradigm, then centration, and to bring about a separation of the

Y84
 Batmanghelidj: Pain: A Need for Paradigm Change

sensation of thirst from hunger; confusion of these sen- 9) HEMPLING. H.G_; OSMOSIS: mE PUSH AND PULL OF
sations may be the causative factor in over-eating. h LIFE; PP. 205-214. BIOPHYSICS OF WATER EOS. FELIX FRANKS
AND SHEILA F. MATHIAS. JOHN WILEY AND SONS LTD. I982.
was found that an effective volume and timing for
10) MEDAWAR. P.B. AND J.5. MEDAWAR; ARISTOTI..E TO
wmer intake, as a rreatment procedure in clinical- was; PP. 279-281. HARVARD.1983.
ly diagnosed peptic ulcer disease, was one full glass II) SCHWARZ. JEAN-CHARLES; HISTAMINE AS A TRANS-
of water half an hour before a meal and another MIlTER IN BRAIN; MINIREVIEW. LIFE SCIENCES. VOL. I 7.
glass two and a half hours after a meal: that is six PP. 503-518. 1975.
12) SNYDERS.H.; BROWN. B. AND KUHAR. M.J.; 111E
glasses of water, approximately one and one half
SUBSYNAPTOSOMAL LOCAllZATION OF HISTAMINE HIS·
liters, per day (1,2,25). It was also found that with TIDINE DECARBOXYLASE AND HISTAMINE
regular intake of water, the thirst sensation becomes METI-lYLTRANSFERASE IN RAT HYPOTHALAMUS; 1.
NEUROCHEMISTRY. VOL.23. PP. 37-45. 1974.
more pronounced and recognizable by the patients
13) BEAVEN. MICHAEL A.; FACTORS REGULATING
who did not acknowledge their thirst before. As AVAILABILITY OF HJSTAMrNE AT TISSUE RECEPTORS; PHAR-
a grass root phenomenon, and in view of presented new MACOLOGY OF HISTAMINE RECEPTORS. EDS.
perspectives. the role of free water deficiency in can- C.R.GANELLIN & M.E.PARSONS. WRIGHT.PSG.PP. 103-139.
1982.
cer transfom1ation warrants investigation (25, un-
14) AFFOLTER.H.; PEYER. M. & PLETSCHER. A.;
puhlished Iheoretical research); and it certainly deser- STORAGE OF BIOOENIC AMINES LN GUINEA-PIG BRAIN
ves <tpplit:ation as a preventive measure. The final con- SYNAPTOSOMES: INFLUENCE OF PROTON GRADIENT AND
clusion seems to be the importance of regular water in- MEMBRANE POTENTIAL; BR. 1. PHARMAC. 78,111-116.1983.
15) GERALD. M.C; AND MAICKEL, R.P.; STUDIES ON THE POS-
take regardless of thirst. The cell, it seems, is just
SI13LE ROLE OF BRAIN HISTAMINE IN BEHAVIOUR. BRJ.PHAR-
like a city thaI TUns on hydro-electric power, it needs MAC. 44, PP. 462-471. 1972.
the "water head" over the cation pumps of the 16) LEIBOWITL.SARAH FRYER; HISTAMINE: A STIMULATORY
lllcmbr:l1lc barrier for generation of energy and EFFECT ON DRINKING BEHAYlOR IN RAT; BRAIN RESEARCH,
63, PP. 440-444. jl"J73.
its utilization, just like a "pump storage dam."
After all, the initial progenitor cells used the same 17) KRALY. F.SCOTT; HISTAMINE PLAYS A PART IN INDUC-
,rhysical Jaws when they lived in sea waler. TION OF DRfNKlNG BY FOOD INTAKE; NATURE VOL. 302. PP. 65-
/i6. :3 MARCH 19R3.
18) KRALY. F.SCOTT; MILLER. L.A. AND HECHT. E. S.;
Acknowledgement. thank The Allmighty for HISTAMINERGIC MECHANISM FOR DRINKING ELICITED BY IN-
SULIN IN THE RAT; PHISIOLOOY AND BEHAVIOR. VOL.]I, PP.
his "light and fine detailed guidance" that has made 233-236, 1983.
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and suffering of his 'creations he has tried to guide YAGALLY MEDIATED HISTAMINERGIC COMPONENT or
liS yet again DRINKING ELICITED BY EATING IN THE RAT; BEHAVIORAL
t\ElJROSCIENCE. VOL. 98 NO.2. PP. 249-255, 1984.
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989