Opioid Analgesics

H.Y Yang
Institute of Pharmacology, NYMU

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 Opioid & Opiopeptin
 Opioid 類嗎啡樣物質 :
a. all drugs, natural & synthetic, with morphine-like
action (opiate )
b. all exogenous substances that bind
specifically to any subtype of opioid receptor and
produce some agonistic action

 Opiopeptins 類嗎啡樣多胜: all endogenous

opioid peptides ( -endorphin, Leu-enkephalin, Met-
enkephalin, Dynorphin, etc )

 Narcotic : imprecise term

 opioid system : 4 major opioid receptors

1. Sensory, GI, endocrine, ANS
2. Emotion : rewarding and addictin
3. cognitive : leaning & memory 2
 Pain痛覺 & nociception傷害性感受
 Definition :實質或潛在的組織之直接傷害或有關此傷害所敘述之不愉快的感覺和情緒
的經歷；大多數我們所謂之痛，包括情緒上的反應，都是主觀、後天學來的，不是本
能的反應。
 "poine" in Greece, "poene" in Latin, meaning "penalty贖罪" or "punishment" from the gods. Pain is a
complex experience encompassing sensory, affective, and cognitive elements.病患多用比喻性字眼
形容；如偏頭痛會說好像有人用針刺我的眼睛。我們報告刺傷的痛楚時，想像一把利
刀直刺入肌膚，而那些曾被刺傷的所表達的是完成不同之感覺；不是強力快速刺入，
而像被揮一拳後，久久不能散去。如凍傷後2~3分鐘後所呈現的是燒炙感，接著是疼痛
感。
 Acute, chronic & neuropathic pain
Referred pain 牽連痛for visceral pain
Hyperalgesia 痛覺過度
Phantom pain 截肢幽靈痛
Allodynia 觸物感痛
Compartment :
1. Sensation 感覺 & sensitization 致敏 nociception傷害性感受 ;
2. Recognition 認知
3. Discrimination 辨識
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 Pain sensation
 Mixed function polymodal nociceptor : type C , A fiber
1. thermoreceptor :vanilloid receptor subtype 1 (VR1 or capsaicin receptor , a ligand-gated, non-
selective cation channel) which is involved in noxious heat
2. Chemosensitive nociceptor and algesic致痛substance: K+, 5-HT ( 5HT1a ), PGs, kinins, ATP,
NMDA (not hist), nerve growth factor, neuropeptides (Sub.P, calcitonin gene-related peptide,
IL-1( IL-1), neutrophil-chemotactic peptides, and NGF-octapeptide
3. TTX-resistant Na+ channel ( Nav1.8 , termed PN3 or sensory-neuron specific, SNS) may play
a key role in neuropathic and chronic inflammatory pain
4. PKC-knock-out mice display intact acute pain responses but reduced thermal and mechanical
allodynia after nerve injury.
Tissue injury induced hyperalalgesia ( receptor hypersensitivity ) involved
A. Neuronal factor ( NMDA, sub. P , neurokinin-1)
B. Ciculating factors ( TNF-, IL-1 )
C. Kinases ( PKC) , PLase-A2, COX2
D. Channels ( Ca, TTX-resistant Na ) &
receptors ( NMDA )
PG & sub. P: enhance sensitivity,
NOT direct excitation

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5
Molecular mechanisms involved in pain

 Transcription factors and second messenger molecules :

expression of c-fos, CREB ( cAMP response element binding protein ), ERK
(extracellular signal-regulated protein kinases ) as a molecular marker for
noxious stimulation
 Neurotrophic factors (neurotrophins) : NGF (nerve growth factor),
GDNF ( glial-cell-derived neurotrophic factor ) & BDNF (brain-derived neurotrophic
factor )
 Cytokines and inflammatory pain : Pro-inflammatory ( TNF-, IL-1,
IL-6, IL-8, etc) and anti-inflammatory ( IL-4, IL-10, IL-13, etc.) cytokines

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 傷害性信息上行傳導路徑
 Med (Paleo) ST tract, relays in reticular
formation to Intralaminar thalamic N.
and end in limbic system ( ant.
Cingulate gyrus) : polysynaptic, diffuse,
emotional component involved, lack of
somatotopic representation

 The majority of these spinal m- & -

receptor ligand-binding sites are
located presynaptically on the terminals
of primary afferent nociceptors.

 Neurotransmitter in
PAG : 5-HT, NT, SP, VIP, Enk,
Dyn, GABA.
NRM : Enk, SP, SOM, TRH ,5HT
( colocalized with Enk )
LC : NA ( 2 ), NPY, galanin.
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 Pain Recognition
 上行性路徑 :
Primary sensory component of m-opioid receptor :
ipsilateral nucleus accumbens and amygdala
pain-specific affective component of m-opioid
receptor : dorsal anterior cingulated
 旁支: Enkephalinergic local circuit
neuron could "gate" the activation of
the spinothalamic pathway
 牽連: Neurochemical changes in
sensory neurons and spinal cord, e.g.
Inflammation sub P & CGRP in SG
Neuropathy  sub P & CGRP; where
galanin, NPY, GAP-43 
Bone cancer  glial fibrillary acidic protein
( GFAP ) 
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 Opioid receptor-evoked cellular responses
Direct G-protein  or a subunit-mediated effects
activation of an inwardly rectifying K channel
inhibition of voltage operated Ca channels (N, P, Q and R type)
inhibition of adenylyl cyclase
Responses of unknown intermediate mechanism
activation of PLA2 , PLC ( possibly direct G protein  subunit activation), MAPKinase, large conductance Ca-activated K channels,
L type voltage operated Ca channels,
inhibition of T type voltage operated Ca channels
direct inhibition of transmitter exocytosis
Responses which are a consequence of opioid-evoked changes in other effector pathways
activation of voltage-sensitive K channels (activation of PLA2)
inhibition of M channels ( activation of PLA2)
inhibition of the hyperpolarisation-activated cation channel (reduction in cAMP levels following inhibition of adenylyl cyclase)
elevation of intracellular free Ca levels (activation of PLC, activation of L type voltage operated Ca conductance)
potentiation of NMDA currents (activation of protein kinase C)
inhibition of transmitter release (inhibition of adenylyl cyclase, activation of K channels and inhibition of voltage operated Ca channels)
decreases in neuronal excitability (activation of K channels)
increases in neuronal firing rate ( inhibition of inhibitory transmitter release - disinhibition)
changes in gene expression : long-term changes in adenylyl cyclase activity, elevation of intracellular Ca levels, activation of cAMP
response element binding protein (CREB)

 unique receptor mechanisms are achieved through alternative splicing within

its C terminus :
1. k and  opioid receptors have been shown to exist as homodimers & heterodimer to alter their pharmacological
properties
2. m and  receptors recognize principally the Tyr-Gly-Gly-Phe core of the endogenous peptide, whereas the k receptor
requires this core and the arginine in position 6 of dynorphin A and other prodynorphin products

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Pain Discrimination
 Descending inhibitory pathway : med &
intralaminar thalamic N , PAG , through
dorsal raphe magnus (NRM), Nucleus
reticularis gigantocellularis (NRGC) to
dorsolat. funiculus to laminar I, II of spinal
dorsal horn.
 Pain experience involved in primarily
sensory (e.g., ipsilateral nucleus
accumbens and amygdala) or affective
and unpleasantness (e.g., dorsal
anterior cingulate, prefrontal cortex )
components in the brain
 Opioid peptides and their receptors
are found throughout these
descending pain control circuits

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 Pain anatomy system
 痛覺之接受 ( perception of pain) : laminae I and II of the spinal
cord, the spinal trigeminal nucleus, and the periaqueductal gray
 感受與行為(affective behavior)之調適 : amygdala, raphe
nucleus, hippocampus, locus ceruleus, and the frontal cerebral
cortex
 動作( motor control )之調適 : caudate nucleus and globus
pallidus
 自主神經之協調: medulla oblongata
 神經內分泌之協調 : median eminence.
 Sites of opioid (MOR )-induced analgesia :
a) Endorphins are found in all regions where pain is modulated, i.e. the
descending inhibitory pathway and the peripheral tissues.
b) Periaqueductal gray (PAG)
c) Nucleus raphe magnus (NRM)
d) Spinal cord dorsal horn, trigeminal nerve 11
 Action site in CNS
Localization Functions
Spinal Cord: Laminae I,& II modulation of pain perception
Brain Stem: Sub. gelatinosa of spinal tract of caudal trigeminal N. modulation of pain perception
N. solitary Tract, N commissuralis, N ambiguus taste, vagal reflex, cough suppression, respiration,
orthostatic hypotension, inhib. of gastric secretion,
EEG synchronization and sleep induction
Area postrema nausea and vomiting
Locus ceruleus arousal, attentiveness, muscle inhibition during REM
sleep
Habenula-interpeduncular N-fasciculus retroflexus emotional behavior, site of action between limbic
area and basal ggl
Pretectal area ( Med. & Lat optic N. ) Upward eye movements and pupillary reflexes
Superior colliculus Orienting movements of head & eyes to sensory targets
Ventral N. of lat. geniculate central modulation of visual input
Dorsal, Lat, med terminal N of accessory optic pathway entrainment of endocrine rhythms by light, fine adjust of
head-eye
Dorsal cochear N modulation of auditory input
Parabrachial N. Resp., breathing pattern, & modulation of taste and pain
Diencephalon: Infundibulum oxytocin and vasopressin secretion
Thalamus : Med Lat N, int.,ext, & intra laminae N, periventricular N modulation of pain and other somatic sensory ,
arousal, attention
Telencephalon : Amygdala emotional , fear and aversively motivated behaviors
Caudate putamen, globus pallidus motor coordination
N. accumbens locomotion, psychomotor ,reinforcing activity
Subfronical organ water balance 12
Interstitial N of stria terminals olfactory control of male sexual behavior
Pain is suffering :
 癌轉移之
1. 骨痛: 持續、鈍、深部痛；夜晚、運動加劇
2. 臟痛: 間歇、悶、拉扯、深部痛；伴有噁心、嘔吐
3. 神經痛: 灼熱、刺麻感；伴有感覺遲鈍

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 Chronic Severe painkiller : Opioids
 Contraindication for head injury
 Neuropathic pain not effective
 1st choice for terminal stage in
cancer –induced pain

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Epidural & subdural injection for Cancer pts

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 Preoperative & adjunctive in anesthesia
 Heart surgery : fentanyl, (i.v.), morphine
(epidural ) for regional anesthesia
Analog der. : Alfentanyl, Sufentanil ,
Remifentanil ( Ultiva , with higher affinity,
rapid recovery, for neurosurgery; elimination
by plasma esterase ) ultra short duration
(duration: 15', T½ : 5' ), resp. depression (1/4 of
morphine, 1/10 of fentanyl )
Illicit analog, e.g.-methylfentanyl "China
White"; 3-methylfentanyl ( more potent than
morphine, lethal dose: mM range.
 Obstetric analgesia : be caution of meperidine
pass cross placenta

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 New analgesics
 Epibatidine
- Source : 南美厄瓜多爾之毒青蛙Epipedobates tricolor表皮腺
體萃取之生物鹼
- nonopioid analgesic : n-AChR 4(2)2 receptor agonist, ggl blocker
- Potency : 200-500 X of morphine,
- toxicity : resp. arrest in analgesic dose
- patent : ’93 年由Syntex之 Broka及Corey, Fletcher完成其結
構及全合成

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Chronic pain
 Characteristics :
1. Activation of NMDA Receptors
2. Activation of neurokinin-1 ( NK-I ) Receptors
3. Neurogenic Inflammation
4. Hyperalgesia and Allodynia
 So morphine
1. Not suitable for Migraine
2. Not effective to Neuropathic pain
3. Not recommended for RA

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 情緒影響力
 疼痛之正常反應 : 焦慮、害怕、驚嚇、與
痛苦(suffering)
 疼痛增強之負面情緒 : 恐懼、憤怒、罪惡
感、孤獨與無助
 疼痛舒緩之正面情緒 : 希望、信心、愛、
快樂、生存意念、創造力、嘻鬧
 但情緒反應亦非唯一必備的條件
 Pain may be a symptom of an underlying
problem, and proper treatment may require
more than pain relief.

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Ｒｅｗａｒｄ Ｐａｔｈｗａｙ
RED : Results from self-administration experiments.
BLUE：Results from conditioned place preference
Amyg（Amygdala）
Hipp （Hippocampus）
LH （Lateral Hypothalamus）
mPFC （Medial Prefrontal Cortex）
NAc （Nucleus Accumbens）
PPT（Pedunculo-Pontine Tegmental Nucleus）
VTA （Ventral Tegmental Area）
Endogenous reward center ( e.g. VTA, NAc, mPFC,
Lat. hypothalamus, Olfactory tubercle,
hippocampus, and Ven pallidum as critical
areas等回饋性原始神經迴路 ) mediated
natural reinforcers (food , sex) and artificial
reinforcers ( drugs )；衍生的 biobehavioral
dysregulation問題如暴食、好賭成性、瘋
狂購物或運動過度等

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Pain Assessment & Clinical Diagnosis
McGill Melzack Pain Questionnaire ( Pain Rating Index ),
Westhaven-Yale Multidimentional Pain Inventory ( WHYMPI ) for chronic pain

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Symptom release or cure ?

 Pain experience
includes sensory ,
affective , and cognitive
dimension.
 In clinical practice :
1. i.m. inj. ( qid ) or patch
2. Patient control analgesia : iv
infusion
3. Recommend : Subdural injection:
with Port-M Cath. system

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 Chronic neuropathic pain
 Colorful symptoms ( 群症狀 ) :
糖尿病、甲狀腺功能低下、尿毒症、營養不良、化療( 長春花鹼、順鉑等)相關
之神經障礙；格巴二氏徵候群、帶狀泡疹後神經痛、進行性神經肌肉萎縮症、
複合式局部疼痛徵候群( CRPS ) 、第I型和缺血性神經病變等等所引發之
hyperalgesia痛覺過度, allodynia觸物痛 , spontaneous pain 無名痛+ paraesthesias感覺
缺失, dysesthesias感覺障礙 與 affective disturbances感覺異常
 Complex Pathophysiology :
1. Change in expression of channel- , receptor-proteins and neurotransmitter production. e.g.
 Type III Na channel  ectopic spontaneous firing , N-type VOC ( esp. 2 sununit ) 
neurotransmitter release
2. Neuronal loss, synaptic reorganization & rearrangement ( e.g. sprouting , „92); glutamate may
damage GABA neuron ( „90)去抑制之興奮
3. CCK, VIP, galanin, NO;  sub. P, Neurokinin A, CGRP (‟94 ) sub. P discharge from
large fiber ,and small fiber release VIP, CGRP & galanin {但allodynia 可能與主要調飾者
NPY及galanin無關, 而CCK則確認會抑制opioid }
4.  neurotrophin;  BDNF (‟99 )

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Neuropathic Pain: A Guide to Comprehensive Assessment. Pain Management Nursing, 5 (4) suppl. 1: 9-18, „04
Diagnosis and Treatment of Neuropathic Pain. Journal of Pain and Symptom Management , 25: 5S ,’03

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Drugs for neuropathic pain

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Adjuvant Therapy for Neuropathic Pain

Medication Starting dosage* Maximum per day*

Carbamazepine (Tegretol)† 200 mg twice daily 1.6 g
Clonazepam (Klonopin)‡ 0.5 mg three times daily 20 mg
Divalproex (Depakote)‡ 10 mg per kg per day 60 mg / kg
Gabapentin (Neurontin)§ 100 mg three times daily 3.6 g
Lamotrigine (Lamictal)† 50 mg once daily 500 mg
Phenytoin (Dilantin)‡ 100 mg three times daily 600 mg
Baclofen (Lioresal)§ 5 mg three times daily 80 mg
*--Reduce dosage in children and the elderly.
†--Reduce dosage in patients with hepatic and/or renal impairment.
‡--Reduce dosage in patients with hepatic impairment.
§--Reduce dosage in patients with renal impairment

COMMON TARGET : Na Channel

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New Intervention for Neuropathic Pain
 GluR5 receptor antagonist : Ketamine, memantine, and dextromethorphan derivatives.
1. In chronic pain, the phenomenon of "wind-up", can be abolished with CPP.
2. The major limitation with NMDA antagonists is that their psychotomimetic actions
provide unacceptable risk-benefit profiles.
3. LY382884, exhibited antinociceptive actions without ataxia.
 P2X3 receptor antagonist :
1. selectively localized to sensory pathways in trigeminal, nodose, and DRG .
2. P2X3 receptor knock-out mice display reduced nociceptive responses.
3. Suramin are antinociceptive
 Acid Sensing Ion Channels (ASIC's) blocker :
1. ASIC3 (DRASIC) and ASIC-ß are selectively expressed in sensory ganglia and/or the
spinal cord.
2. Amiloride derivatives
 Voltage-dependent Na channel blocker : c-fiber specific TTX-resistant
1. novel subtypes of voltage-gated Sodium channels rNav1.5a
2. lamotrigine and gabapentin ( anticonvulsant ) & amitriptyline ( antidepressant )
derivative

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 Morphine "window into the brain"
 Morpheus: in Greek means the son of god of
dreams ( Somnus )
 Gk. Opion = poppy juice
 The alkaloid isolated from unripe seedpod of
Papaver somniferum
 Indications :
1. severe burn, postoperative and chronic pain ( >
6M )associated with renal or biliary colic, malignant disease
( e.g. cancer ), and acute myocardial infraction
Contraindication for head injury where there is a potential
for raised intracranial pressure
2. acute pulmonary edema :Nitroglycerin is more effective
3. preoperative medication and adjunctive agents in
anesthesia
4. Heart surgery & anesthesia : fentanyl, i.v., morphine
(epidural ) for regional anesthesia
Obstetric analgesia : be caution of meperidine pass cross
placenta
5. maintenance programs for addicts : e.g. methadone, LAAM
( L--acetyl-methadol), buprenorphine, dihydroetorphin
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 Mood effect
 Euphoria : “rash” followed by a
“ high” ( as a “ +” reinforcer )
 Tranquility & sleepiness : “ nod “
 Last about 3-5 hr.
 令人飄飄欲仙的感官奇旅，
不可思議的罪惡幻夢!

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 Opioid Effect
1. GI Constipation : act on myenteric plexus, inhibiting propulsive peristaltic contractions.
Characteristics : little tolerance develops, stimulative laxatives are almost
always prescribed as an adjuvant medication to pt‟s with chronic pain . A newer
therapy involves the co-administration of IV morphine with oral naloxone in addition to
stimulative laxatives.
2. Nausea : directly stimulate the chemoreceptor trigger zone for emesis in the area
postrema of the medulla.
Characteristics : Since the incidence of nausea is so high (about 50%), antiemetics
are prescribed as an adjuvant medication in about 2/3 of patients . To treat
nausea: cholinergic such as scopolamine, or dopamine antagonists such as
droperidol and ondansetron are often used .
3. Sedation : caution with drug interaction with alcohol, hypnotics
4. Pruritus (itching) : Occurs more frequently with epidural or intrathecal , not a drug allergy,
due to histamine release from the mast cells. Treatment : antihistamine and low dose
naloxone
5. Miosis : excite the oculomotor nerve. Not develop tolerance, Usually it does not interfere
with the patient‟s vision.

–continuous30
6. Confusion, hallucinations : a problem with mixed agonists-antagonists ( e.g.
pentazocine, butorphanol, or Nalbuphine). Elderly patients are much more
susceptible. Hydromorphone and meperidine are usually better tolerated in those pts.
7. Euphoria : as a desired therapeutic effect in terminal pain, but many patients experience
dysphoria instead. IV injection has a much higher incidence .
8. Hypotension : with rapid iv morphine, meperidine, and hydromorphone . Fentanyl would
be the preferred analgesic agent in patients with compromised hemodynamics.
9. Respiratory depression : The most important adverse effect , Mediated at brainstem
respiratory centers, reduce responsiveness of respiratory centers to increase in
PCO2. as a intoxication marker( dose-dependent fashion).
10. The Toxicity triad
a) Catastrophic respiratory depression, as low as 2-4 breaths per minute: patient may
be conscious
b) Stupor or coma
c) Pinpoint pupils
Treatment : IV inj naloxone

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Meperidine (Pethidine, Demerol): prototype of synthetic
phenylpiperidine
 劑量 : 1/10 x, short duration (T½ :2-4 hr), atropine-like ( higher incidence of nausea
and vomiting than morphine).
 使用於: It should be used only for short-term ( <48 hr, < 600 mg/D )treatment of
acute pain, It‟s a poor choice in the management of cancer pain
 注意: In patients taking a MAO inhibitor, meperidine can cause excitation,
convulsions, hyperpyrexia, respiratory depression , hypotension, even severe
encephalopathy and death
 similar euphoric effect, less antitussive, constipation, urinary retentionl, short intense
withdrawal
 normeperidine (demethylated excitatory metabolite): > 200 mg, p.o. induce
hallucination tremor & m. twitch rather than sedation. { naloxone insentive; diazepam
or phenytoin sensitive }
 medical professions are most frequently subjected to meperidine dependence
 衍生物 : MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), an analogue of
meperidine, a by-product that was formed during synthesis of MPPP. Is was found in
San Jose, Califoria, 1982 as a neurotoxin and selective destroys neuronal tracts in
sub. nigra and induced Parkinsonism. 32
33
Fentanyl: phenylpiperidine der. synthetic

 50~100 x ( tail flick test 295 x ), rapid onset ( crosses the BBB easily , peak : 3~5
min , T½ : 20' )
 selective mu receptor agonist
 S.E.: muscle rigidity in therapeutic doses
 Clinical Use: cardiac anesthesia( iv, epidural & intrathecal ), and cause less
hemodynamic disruption ( without histamine release) than morphine
 neuroleptic analgesia (+ droperodol :Inovar) with nitrous oxide for anesthesia by
Stanlegused in 1978
 analog der. : Alfentanyl, Sufentanil , Remifentanil ( Ultiva , with higher affinity,
rapid recovery, for neurosurgery; elimination by plasma esterase ) ultra short
duration (duration: 15', T½ : 5' ), resp. depression (1/4 of morphine, 1/10 of fentanyl )
 Illicit analog, e.g.-methylfentanyl "China White"; 3-methylfentanyl ( more potent
than morphine, lethal dose: mM range.

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Pentazocine (Talwin, 速賜康 ), benzomorphane der.
1967, Partial angonist, p.o.

 kappa agonist, mu receptor antagonist; spinal analgesia,

 more rapid onset and a short duration than morphine , potency = 1/3 morphine
 psychomimetic : dysphoria with nightmare & hallucination, rather than euphoria
are the most predominant psychomimetic effect
 T's+B's ( pentazocine 50 mg + tripelennamine 50 mg): immediate "flash" or
euphoria, followed a "well-being" for 4-6 hr
 a ceiling ( i.e. limitation) to analgesic effect ; At higher doses, it causes only a
slight resp. depression
 Toxic symptoms ( > 60 mg)
Behavior: anxiety, feeling of depersonalization, nightmare, visual hallucination
Respiration: dec resp rate & tidal vol, incr PCO2 level, apnea
Cardiovascular: incr systolic & diastolic BP, tachycardia
Nonspecific: nausea, vomiting, dizziness, lethargy, paresthesia, abdominal pain,
tonic-clonic seizure
 Clinical: not use in cancer-induced pain by p.o., poor oral efficacy, psycomimetic,
& ceiling effect. 35
Tramadol ( Ultran )

 orally effective for moderate to moderalely severe pain

 Not chemically related to opiates, an centrally acting
analgesic,
 bind to mu- opioid receptor, inhibit 5-HT & NE uptake,
 low abuse liability ( may be due to the delay necessary
for metabolism)
 less respiratory depression than opiates
 dizziness, somnolence, nausea, constipation, sweating
and pruritis.

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ANTAGONISTS : Naloxone ( Narcan ) & Natrexone (Trexan)

 mu receptor specific antagonist ( 1-4 nM for mu, 5-15 nM for kappa, 15-40 nM for
delta receptor, mu : delta : kappa = 1: 15 : 40 ); GABA antagonist at high conc.
 short T 1/2, repeat inj
 reverse resp. depression, hypotension in spinal and endotoxic shock
 precipitates abstinence ( 0.4-0.8 mg, iv, 2-3 dose/2-3 min ). Be caution of the
"overshooting phenomenia"
 Na shift theroy: increase [Na+] cause antagonist binding inc, agonist binding dec
 Analog & Specific antagonists:
1. Natrexone (Trexan): p.o., long acting ( T1/2= 10 hr ), for heroin dependence &
alcoholism
2. Nalmefene, Cypridime, ß-funaltrexamine : specific for mu receptor
3. Naltrindole : specific for delta receptor
4. Nor-binaltorphimine : specific for kappa receptor

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Selectivity of opioid drugs and peptides for different receptors
Compound m  k 
Opiopeptins
-endorphin 3+ 3+ -
Leu-enkephalin 2+ 3+ - -
Met-enkephalin 2+ 3+ - -
Dynorphin 2+ 3+ -
Opioid drugs
Morphine 3+ 1+ -
Fentanyl 3+ -
DMAGO 3+
Sufentanil 3+ 1+ 1+ -
Methadone 3+
Etorphine 3+ 3+ 3+ -
Codeine 1+ 1+ 1+ -
Meperidine 2+ 1+ 1+ -
Pentazocine 1 1+ 2+ 1+
Cyclazocine 1 1+ 2+ 1+
Nalorphine 2 2 2 1+
Buprenorphine 3 - - -
Meptazinol 2 - - -
Naloxone 3 2 2 -
Natrexone 3 2 2 -
+ : agonist; : antagonist; : partial agonist

38
 Chronic adverse effects & intoxication
 addition, tolerance, psychological & physical dependence, constricted pupils,
constipation or diarrhea, skin infection, scars, abscess.
Extent of tolerance developed to some of the effects of the opiates -------
High degree Moderate degree Minimal or No
Analgesia Bradycardia Miosis ( pinpoint pupils)
Euphoria, Dysphoria Constipation
Mental clouding Convulsion
Sedation Antagonist effect
Resp. depression
Antidiuresis
Nausea, Vomiting
Cough suppression
 Not to be confused with “addiction,” a negative term associated with psychological
dependence and addictive behavior.

39
Tolerance

a) Defined as a gradual loss in effectiveness with frequently repeated administration

b) Marked tolerance develops to the analgesic, euphoric, and respiratory depressant
effects of mu agonists
c) Tolerance does not develop to morphine-induced miosis and constipation
d) No tolerance develops to antagonists
e) Cross-tolerance develops between drugs that act at the same receptor types, e.g.
pts tolerant to morphine are tolerant to the other opioid agonist drugs. Cross tolerance
may not be complete, and therefore one needs to be more careful when switching
from one opioid to another.
f) Tolerance is often mistaken for worsening pathology that then leads to dose escalation.
g) For unknown reasons, pain actually contributes to tolerance of the respiratory system. Thus,
if the cause of the pain is eliminated, tolerance may not protect the patient from opioid
toxicity. In such cases, the opioid dose must be reduced quickly.

40
Withdrawal脫癮( Abstinence戒斷, Rebound hyperexcitability ) Syndrome
 Diagnosis: Himmelbach Scoring System of Abstience Syndrome of morphine ( methadone)
Criteria :  3 of 1). dysphoric mood 2).nausea or vomiting 3) muscle ache 4) lacrimation or
rhinorrhea 5) pupillary dilation, piloerection, or sweating 6) diarrhea 7) yawning 8) fever 9)
insomia
 Unlike the sedative-hypnotic drugs, opioid withdrawal symptoms are seldom life-threatening
 action site: locus ceruleus( LC ) is postulated to play a critical role in feeling alarm,
panic, fear, and anxiety ( negative-reinforcement ) in morphine  clonidine , opioid
Grade Sign Time after last dose
0 Craving, anxiety 6 (12) hr
1 Yawning呵欠, perspiration流汗, running nose流鼻涕, lacrimation流淚 14 (34-48 )
2 Incr above sign + mydriasis散瞳, piloerection豎毛 (gooseflesh雞皮疙瘩)
tremor, hot-cold flushes, aching m & bone, anorexia食慾不振 16 (48-72)
3. Incr above sign + insomia, incr BP, BY, Resp rate &
depth, restlessness, nausea 24-36
4. Incr above sign + febrile發燒facies, position (curled
up on hard surface), vomiting, diarrhea, weight
loss, spontaneous ejaculation or organism, leuko-
cytosis, eosinopenia, blood sugar incr 36-48

 Morphine or heroin withdrawal syndrome: Onset: 6-10 hr, peak: 36-48 hr, duration : 5 D
methadone withdrawal : Onset : 12-48 hr, peak 6 d, less serious, duration: 2 weeks
methadone + Naloxone : Onset : 2-5 min, peak: 10-20 min, duration: 1 hr
meperidine withdrawal : Onset: 3 hr, peak : 8-12 hr, duration: 24 hr, more severe muscle twitching & restlessness, and
fewer ANS signs ( lacrimation, rhinorrhea, yawning, sweating, pupillary dilation) than morphine 41
 Tolerance & PKC
 PKC is key to the development and maintenance of pathological pain states.
1. PKC-mediated phosphorylation of Ca channel associated with the NMDA receptor.
2. Phosphorylation of the μ-opioid receptor by PKC may uncouple the receptor from its
G-protein or alter the properties of its associated K+ channel.
3. activation of PKC decreases μ-receptor mRNA levels, suggesting that PKC also
inhibits μ-opioid-receptor turnover
4. Administration of GM1 ganglioside blocks both the translocation of PKC from cytosol
to membrane and the development of analgesic tolerance to morphine. Additionally,
GM1 ganglioside prevents the development of thermal hyperalgesia associated with
morphine tolerance
 Two G-protein-coupled receptor kinases, β-adrenergic receptor kinase 2 and β-arrestin 2, also
synergistically desensitize μ-opioid receptors.
1. Enhanced analgesia in mice lacking -arrestin 2 .
2. β-arrestin 2 knock-out mice display neither μ-opioid-receptor desensitization nor
tolerance to the antinociceptive effects of chronically administered morphine.
 Opioid tolerance may not be related to receptor desensitization but rather to a lack of
desensitization.

42
43
DRUG DEPENDENCE(藥物依賴性) & Substance Abuse( 物質濫用)
 其衍生的有問題有Tolerance ( 耐受性 ), Sensitization( 致敏性或 reverse tolerance ),
Dependence(依賴), 及Withdrawal ( 脫癮 )；牽涉之惡性循環有preoccupation-
anticiptation(先入為主), binge-intoxication( 沉迷中毒) 及 withdrawal-negative ( 脫癮負
向)
 Physical dependence & withdrawal是某些濫用藥物(非必備)衍生的問題；但其核心
問題是psycho-dependence之craving 與relapse 之難以克服.
 endogenous reward center ( e.g. VTA, N accumbens, prefrontal cortex, Lat. hypothalamus,
Olfactory tubercle, hippocampus, and Ven pallidum as critical areas等回饋性原始神經迴
路 ) mediated natural reinforcers (food , sex) and artificial reinforcers ( drugs )；衍生的
biobehavioral dysregulation問題如暴食、好賭成性、瘋狂購物或運動過度等。 e.g.
Positive motivational effects of opioids are mediated partially by dopamine release
at the level of the NAcc.
 CERB (cAMP-response element binding protein) -like binding protein regulated the c-fos,
BDNF , RGS4 ( regulator of G-protein signaling 4 ) gene expression為重心
u Reduction the CREB in the nucleus accumbens enhancing reward (Science 282: 2272, 1998 )
 NPY mRNA ( gene expression ) is significantly increased in striatum, not in hippocampus
 uncoupling of receptor from effectors, e.g. adenylate cyclase等G protein調節性訊息。
 -arrestin-2導致m receptor之desensitization 與morphine 之 tolerance有關， 但與
dependence 無關( Nature 408: 720-723, 2000 )
 Long-term adaptation : G protein receptor kinase(GRKs), arrestins, G protein -subunits44:
phosducins ,
45
46
47
48
49
 Schedule I
1-(1-Phenylcyclohexyl)pyrrolidine : PCPy, PHP, rolicyclidine 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine : PEPAP, synthetic heroin
1-[1-(2-Thienyl)cyclohexyl]piperidine : TCP, tenocyclidine 1-[1-(2-Thienyl)cyclohexyl]pyrrolidine : TCPy
1-Methyl-4-phenyl-4-propionoxypiperidine : MPPP, synthetic heroin 2,5-Dimethoxy-4-ethylamphetamine : DOET

2,5-Dimethoxyamphetamine : DMA, 2,5-DMA 3,4,5-Trimethoxyamphetamine : TMA

3,4-Methylenedioxyamphetamine : MDA, Love Drug 3,4-Methylenedioxymethamphetamine : MDMA, Ecstasy, XTC
3,4-Methylenedioxy-N-ethylamphetamine : N-ethyl MDA, MDE, MDEA 3-Methylfentanyl : China White, fentanyl

3-Methylthiofentanyl : Chine White, fentanyl 4-Bromo-2,5-dimethoxyamphetamine : DOB, 4-bromo-DMA

4-Bromo-2,5-dimethoxyphenethylamine : Nexus, 2-CB, sold as Ecstasy 4-Methoxyamphetamine : PMA
4-Methyl-2,5-dimethoxyamphetamine : DOM, STP 4-Methylaminorex (cis isomer) : U4Euh, McN-422

5-Methoxy-3,4-methylenedioxyamphetamine : MMDA Acetorphine

Acetyl-alpha-methylfentanyl : Acetylcodone Acetyldihydrocodeine
Acetylmethadol : Methadyl acetate Alphacetylmethadol except levo-alphacetylmethadol
Allylprodine

Alpha-Ethyltryptamine : ET, Trip Alphameprodine

Alphamethadol Alpha-Methylfentanyl : China White, fentanyl
Alpha-Methylthiofentanyl : China White, fentanyl Aminorex : has been sold as methamphetamine

Benzethidine Benzylmorphine
Betacetylmethadol Beta-Hydroxy-3-methylfentanyl : China White, fentanyl
Beta-Hydroxyfentanyl : China White, fentanyl Betameprodine

Betamethadol Betaprodine
Bufotenine : Mappine, N,N-dimethylserotonin Cathinone : Constituent of "Khat" plant
Clonitazene Codeine methylbromide

Codeine-N-oxide Cyprenorphine
Desomorphine Dextromoramide : Palfium, Jetrium, Narcolo
Diampromide Diethylthiambutene

Diethyltryptamine : DET Difenoxin : Lyspafen

Dihydromorphine Dimenoxadol
Dimepheptanol Dimethylthiambutene

Dimethyltryptamine : DMT Dioxaphetyl butyrate

Dipipanone : Dipipan, phenylpiperone HCl, Diconal, Wellconal Drotebanol : Metebanyl, oxymethebanol
Ethylmethylthiambutene Etonitazene

Etorphine (except HCl) Etoxeridine

Fenethylline : Captagon,amfetyline,ethyltheophylline amphetamine Furethidine
Gama Hydroxybutyric Acid (GHB) : gama hydroxybutyrate, Na oxybate Heroin : Diacetylmorphine, diamorphine

Hydromorphinol Hydroxypethidine
Ibogaine : Constituent of "Tabernanthe iboga" plant Ketobemidone : Cliradon
Levomoramide Levophenacylmorphan

Lysergic acid diethylamide : LSD, lysergide Marihuana : Cannabis, marijuana

Mecloqualone : Nubarene Mescaline : Constituent of "Peyote" cacti
Methaqualone : Quaalude, Parest, Somnafac, Opitimil, Mandrax Methcathinone : N-Methylcathinone, "cat"

Methyldesorphine Methyldihydromorphine 50
Morpheridine Morphine methylbromide
Morphine methylsulfonate Morphine-N-oxide CONTINOUS………
Myrophine N,N-Dimethylamphetamine
N-Ethyl-1-phenylcyclohexylamine : PCE N-Ethyl-3-piperidyl benzilate : JB 323
N-Ethylamphetamine : NEA N-Hydroxy-3,4-methylenedioxyamphetamine : N-hydroxy MDA
Nicocodeine Nicomorphine : Vilan
N-Methyl-3-piperidyl benzilate : JB 336 Noracymethadol
Norlevorphanol Normethadone : Phenyldimazone
Normorphine Norpipanone
Para-Fluorofentanyl : China White, fentanyl Parahexyl : Synhexyl,
Peyote : Cactus which contains mescaline Phenadoxone
Phenampromide Phenomorphan
Phenoperidine : Operidine, Lealgin Pholcodine : Copholco, Adaphol, Codisol, Lantuss, Pholcolin
Piritramide : Piridolan Proheptazine
Properidine Propiram : Algeril
Psilocybin : Constituent of "Magic mushrooms" Psilocyn : Psilocin, constituent of "Magic mushrooms"
Racemoramide Tetrahydrocannabinols : THC, Delta-8 THC, Delta-9 THC and others
Thebacon : Acetylhydrocodone, Acedicon, Thebacetyl Thiofentanyl : Chine white, fentanyl
Tilidine : Tilidate, Valoron, Kitadol, Lak, Tilsa Trimeperidine : Promedolum

51
Key neural circuits of addiction
Dotted lines indicate limbic afferents to the nucleus accumbens (NAc).
Blue lines represent efferents from the NAc thought to be involved in
drug reward.
Red lines indicate projections of the mesolimbic dopamine system
thought to be a critical substrate for drug reward. Dopamine neurons
originate in the ventral tegmental area (VTA) and project to the NAc
and other limbic structures, including the olfactory tubercle (OT),
ventral domains of the caudate-putamen (C-P), the amygdala (AMG)
and the prefrontal cortex (PFC).
Green indicates opioid-peptide-containing neurons, which are
involved in opiate, ethanol and possibly nicotine reward. These opioid
peptide systems include the local enkephalin circuits (short segments)
and the hypothalamic midbrain -endorphin circuit (long segment).
Blue shading indicates the approximate distribution of GABA A ( -
aminobutyric acid) receptor complexes that might contribute to
ethanol reward.
Yellow solid structures indicate nicotinic acetylcholine receptors
hypothesized to be located on dopamine- and opioid-peptide-
containing neurons. (ARC, arcuate nucleus; Cer, cerebellum; DMT,
dorsomedial thalamus; IC, inferior colliculus; LC, locus coeruleus; LH,
lateral hypothalamus; PAG, periaqueductal grey; SC, superior
colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum.)

52
Regulation of CREB by drugs of abuse
The figure shows a dopamine neuron of
the VTA innervating a class of GABA
projection neuron from the nucleus
accumbens that expresses dynorphin .
Dynorphin constitutes a negative
feedback mechanism in this circuit:
dynorphin, released from terminals of
the NAc neurons, acts on -opioid
receptors located on nerve terminals
and cell bodies of the DA neurons to
inhibit their functioning. Chronic
exposure to cocaine or opiates
upregulates the activity of this negative
feedback loop through upregulation of
the cAMP pathway, activation of CREB
and induction of dynorphin.

53
 Comparison of mu opioid receptor binding concentrations in a healthy control and a heroin-
addicted volunteer two weeks after detoxification and placebo administration. Large increases in
mu opioid receptor binding are detected in a number of brain regions, most prominently in
anterior cortical regions, such as the prefrontal cortex and anterior cingulate.
54
 Drug Treatment for chronic dependence
1. Methadone ( 1mg can substitute for
4 mg morphine, 2 mg heroin, or 20
mg meperidine ) or -acetyl-
methadol (USA )
2. Buprenorphine ( Buprenex,
Subutex ) substitution (UK, US in
2000 )
3. Etorphine ( China )
4. Ibogaine (Endabuse) :an NMDA
antagonist ( alternative therapy )
Acamprosate ( alternative therapy )
5. Therapeutic Communities治療性
社區 ( adjuvant therapy )

55
 Opioid receptor
 morphine-induced analgesia, reward effect and
withdrawal symptoms in mice lacking the m-opioid-
receptor gene ( Science 383: 819-823, 1996 )
 In the human genome, the gene encoding the 
receptor is located on chromosone 1( mice in 4D), k
receptor is located on the proximal long arm of
chromosone 8, m receptor is located on the distal arm
of chromosone 6.
1. m-opioid receptor mRNA : dorsal root ganglia (DRG),
dorsolateral PAG
2. -Opioid receptor mRNA : ventral and ventrolateral
quadrants of the PAG, the pontine reticular formation,
and the gigantocellular reticular nucleus, but only low
levels are seen in the median raphe and nucleus raphe
magnus.
3. k-Opioid receptor mRNA and ligand binding are
widespread throughout the PAG, pontine reticular
formation, median raphe, nucleus raphe magnus, and
adjacent gigantocellular reticular nucleus. 56
Molecular mechanism of opioid receptor
 MOR : the major molecular target for morphine activity in vivo

MOR-/- : abolition of morphine-induced analgesia, place preference and physical dependence,

as well as morphine respiratory depression and immunosuppression.

By contrast, the analgesic efficacy of heroin and the major morphine metabolite M6G remains
intact in exon 1-deficient mice

 DOR : its activity contributes to improve mood states.

DOR-/- (Deletion of exon 2) : consistent anxiogenic- and depressive-like responses , basal pain
sensitivity is unaffected

 KOR : a prominent role in the perception of visceral pain.

KOR-/- (deletion of the initiation codon and N-terminal coding region ): hyperalgesic for HAc-
induced writhing test
57
 Characteristics of the cloned opioid receptors

Mu (MOR ) Delta (DOR ) Kappa ( KOR )

Effector 7TM; Gi/o coupled 7TM; Gi/o coupled 7TM; Gi/o coupled
Gene organization Intronic Intronic Intronic
6q24-25 1p34.3-36.1 8q11.2
mRNA Size 10-16 kb 4.5, 11.0 kb 5.2 kb
Structure , Human 400a.a 372a.a 380a.a.
Number of glycosylation 5 2 2
mRNA distribution thalamus cortex hypothalamus
striatum striatum N accumbens
locus ceruleus let reticular sub. nigra
N of solitary tract Vent tegmental area N of solitary tract
Selective agonist DAMGO DPDPE U50488
sufentanil DSBUET ICI197067
Selective antagonist CTOP Naltrindole nor-binaltorphine

58
 Action Mechanisms of Opioid Receptor
Increase K+ conductance ( µ inhibit
locus coeruleus by activating an
inward-rectifying K+ current 
hyperpolarization
Inhibit N-type Ca2+ channels ( k in dorsal
root ganglion cells ) inhibit neural
transmission
 Inhibit of ( PGE1, forskolin-induced )
adenylyl cyclase ( µ ,k in different
nucleuslong term adaptation;

59
Delta Kappa

Mu Orphan

60
61
interactions of calmodulin and G proteins with the i3 loop of the µ opioid receptor (MOR). Calmodulin is thought to
block basal G protein coupling, but it is released upon receptor activation by an agonist such as morphine. After
chronic morphine pretreatment, calmodulin is depleted from the plasma membrane, which appears to permit
enhanced access of G proteins to the receptor and, paradoxically, increase basal G protein coupling after
morphine pretreatment. Receptor phosphorylation at S268 (a CaM-kinase II consensus site) might play a role in
regulating access of G proteins and calmodulin. The i3 loop of MOR contains a calmodulin-binding motif in its C
terminal portion, consisting of a predicted amphipathic -helix with several positively charged residues. Adapted
from J Biol Chem. 1999;274:22081-22088; J Neurochem. 2000;75:763-771; J Neurochem. 2000;74:1418-1425.

62
Opiopeptins : Endogenous Opioid Peptides

63
Hans Kosterlitz & Solomon Synder
In 1971, first by Solomon Snyder and his student, Candice Pert of John Hopkins University using a technique developed by Avram
Goldstein of Stanford Univ., to evaluation opiate receptor . That same year two other groups headed by Eric J. Simon of New York
Univ. (1973) and Lars Terenious in Uppsala, Sweden (1973) demonstrated specific opiate binding in nervous tissue. The“ morphine-
like substance“ treasure hunt had begun .
In the mid-1960s Choh Li of the Univ.California at Berkeley had isolated a pituitary hormone which he named B-Lipotropin (Li, 1964).
He noted that one portion of this hormone had analgesic properties. One year after the discovery of the receptor sites John Hughes
at the laboratory of Hans Kosterlitz in Aberdeen, Scotland reported the existence of an endogenous morphine-like substance which
they later purified and named Enkephalin for "in the head" (Hughes, 1975a; Hughes, 1975b; Kosterlitz, 1976) The Aberdeen group
recognized that the peptide sequence of Enkephalin was contained within Li's B-Lipotropin. Li would later name the other
endogenous morphine-like peptides, which also come from his pituitary hormone, Endorphin for "morphine within."
Today all endogenous morphine-like substances, including Dynorphin found by Avram Goldstein (Goldstein, Tachibana, Lowney,
Hunkapiller & Hood, 1979). In 1978 Solomon Snyder, John Hughes and Hans Kosterlitz shared the Lasker Award for their discoveries.

64
 Enkephalin "endogenous analgesics"
 Precursor: pro-enkephalin ( proenkephalin A )
Proenkephalin : 267 aa, 27kD, yields 4 met-enkephalin (Tyr-Gly-Gly-Phe-Met) , 1-leu-enkephalin, 1
hepapeptide (Me-Arg6- Phe7 ) and 1 octapeptide ( Met-Arg6-Gly7-Phe8 )
 Affinity : delta > mu >> kappa , binds to delta-opioid receptors . These receptors are usually
localized on presynaptic vesicles containing neurotransmitters.
 Physiological effects : regulating pain perception and accupuncture analgesia, responses to
stress( negative feedback control of anxiety & fear-related behavior ), aggression and dominance, GI
peristaltic movement
 Distribution:
1. 1. CNS: widely, interneuron, basal ggl; e.g. perception of pain ( Laminae I & II, Spinal trigemebinal N,
 periaqueductal gray ), modulation of affective behavior ( amygdala, hippocampus, LC & cerebral
 cortex ) , modulation of motor control ( caudate N , globus pallidus ), regulation of ANS ( medulla
 oblongata )& neuroendocrine function ( median eminence )
2. Peripheral : adreneral medulla , enteric N system
 Neuronal function: as neurotransmitter .direct synaptic contact with the spinal cord neurons
 projecting to the thalamus
 ANALOG or derivative
1. synthetic :DADLE
2. enkephalinase inhibitor: kelatorphan, thiorphan, acetorphan

65
Endorphine "endogenous morphine”
 Precursor: pro-opiomelanocortin (POMC) same as corticotropin & melanotropin
POMC: major in ant. & intermed. pituitary, arcuate N., N. tractus solitarius; 267 aa;
POMC precursor of ß-lipotropin, ß-endorphin, adenocorticotropin (ACTH) , -melanocyte-stimulating hormone
(-MSH ) , - MSH
 -Endorphin bears a met-enkephalin sequence at N terminals, however each from different
precursor
 Affinity : mu = delta = kappa, 1). binding to µ-opioid receptors on the presynaptic terminals of
nociceptors and the postsynaptic surfaces of dorsal horn neurons. 2). bind to delta-opioid receptors
on inhibitory interneurons in the substantia gelatinosa of the dorsal horn, causing release of gamma-
aminobutyric acid (GABA)
 Physiological effects:
Antinociception ( icv , spinal) , hyperactivity, seizure, catalepsy & sedation )
Antinociception In supraspinal via epison receptor & Met-enkephalin release; in spinal : via
mu & kappa receptor,
 Distribution: restricted area ( ant & intermed lobe of pituitary, arcuate N of hypothalamus & N
tractus solitarius )
 Neuronal function: as neurohormone
 ANALOG & Derivative :
 Most recently, 2 mu-selective new tetrapeptides , endomorphine-1( tyr-pro-trp-phe-NH2), and
endomorphine-2 ( tyr-pro-phe-phe-NH2) were isolated from bovine brain. ( Zadina JE, Hackler L,66Ge
L-J, Kastin AJ. Nature 386: 499-502, 1997 )
 Dynorphin 強啡
 Isolated from porcine pituitary, active form : A (1-17) cleaved to B (1-13)
 Precursor : prodynorphin ,widespread distribution
 * 254 aa, bears of 3 Leu-enkephalin, dynorphin,
dynorphin N and -neoendorphin
 Affinity : kappa > mu >> delta , via activates kappa-opioid receptors and
leads to closure of N-type calcium channels
 Physiological effects:
1. Lack of analgesia (icv); biphasic antinociceptive response ( intrathecal ).
2. inhibiting pain signals in acute injury, but having an intensifying effect on
neural transmission in persistent, chronic pain.
3. modulated in chronic inflammation rather then direct action, reduced the
SE in dependent, enhance psychological
 Distribution: widely, synapsed directly onto the thalamic projection neurons,
spinal interneuron
 Neuronal function: neuromodulator
Dynorphin A(1–17) and its excitatory metabolites(1-13) potentiation
NMDA-activated current interact with a glycine-binding site on the
NMDA receptor and with the glycine residues in positions 2 and/or 3.
 twin phosphorylation and dephosphorylation reactions of promoter genes
CREB and TATA regulate the transcription of dynorphin.

67
Selected Reading

 Willis W (ed). Hyperalgesia and Allodynia. Raven

Press, New York, „92
 Max M (ed ). Pain 1999- An updated review. IASP
Press, „99
 Hunt SP, & Mantyh PW. The molecular dynamics of
pain control. Nature Rev. Neurosci. 2: 83- 91, „01
 Waldhoer M, Bartlett SE & Whistler JL. Opioid
Receptors. Annu Rev Biochem. 73: 953-90, „04

68