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Why pain? Because at least some of the receptors of heat and cold — when the
stimulus exceeds a certain threshold — transmit signals that the brain interprets as
pain.
The Receptors
Few, if any, of the receptors of heat, cold, and pain are specialized transducers (in
the way that, for example, the Pacinian corpuscle is). Rather they are sensory
neurons whose plasma membrane contains transmembrane proteins that are ion
channels that open in response to particular stimuli. A single neuron may contain
several types of these ion channels and thus be able to respond to several types of
stimuli. Like all sensory spinal neurons, their axons travel to a dorsal root ganglion
of the spinal cord, where their cell bodies reside, and then on in to the gray matter
of the spinal cord. [View]
Aδ ("A-delta") fibers
o These are thinly-myelinated.
o They transmit signals in response to heat and touch. If the stimulus
exceeds a certain threshold, the brain interprets these as acute pain.
This is "good pain" because it warns you to do something to take care
of the problems, e.g., a hot saucepan.
C fibers
o These are unmyelinated and thus conduct impulses slowly.
Heat
There are several types of ion channels in the skin that respond to temperature.
They are all transmembrane proteins in the plasma membrane that open to
let in both calcium ions and sodium ions (the latter the source of the action
potential). Between them, they cover a range of temperatures.
TRPV4
Warm (~27–34°C)
TRPV3
Warmer (~34–39°C)
TRPV1
Hot (≥43°C). Also activated by capsaicin, the active ingredient of hot chili
peppers, by camphor, by acids (protons), and by pain-inducing products
of inflammation.
TRPV2
Painfully hot (>52°C)
Knockout mice lacking the TRPV1 receptor not only do not avoid water with
capsaicin in it but have a diminished response to heat and to substances that normal
elicit itching.
Birds also have TRPV1 receptors. Theirs also respond to heat (and acids), but do
not respond to capsaicin. This must explain why birds happily eat hot chili peppers
(and so disperse their seeds).
The vampire bat, Desmodus rotundus, expresses normal TRPV1 receptors in the
sensory neurons leading to the dorsal root ganglia, and these respond normally to
painful heat (> 43°C). However, these bats express a shortened version of TRPV1
(produced by alternative splicing) in their trigeminal nerves that run from the bat's
upper lip and nose. The shortened receptors respond to a lower temperature
(~30°C) enabling the bats to detect the warmth radiating from the skin of their
victims.
Cold
One, designated TRPM8, is a channel that admits Ca2+ and Na+ in response
to moderate cold (10–25°C) or menthol (the ingredient that gives mint its
"cool" touch and taste). Knockout mice lacking the gene encoding the
TRPM8 receptor do not avoid cold places as normal mice do.
A second, designated TRPA1, responds to lower temperatures (<18°C). It
also responds to several irritant chemicals eliciting signals that the brain
interprets at pain. TRPA1 is found in the hair cells of the inner ear that
respond to sound and changes in position.) However, TRPA1 knockout
mice respond normally to cold and seem to have normal hearing so the
precise role of these receptors is still uncertain for those stimuli.
Pain
When sensory nerve fibers are exposed to extremes, they signal pain. Pain
receptors are also called nociceptors.
Processing Pathways
All the neurons in the skin are part of the sensory-somatic branch of the peripheral
nervous system. Their axons pass into the dorsal root ganglion, where their cell
body is located, and then on in to the gray matter of the spinal cord where they
synapse with interneurons. [View]
Neuropathic Pain
This is pain caused by injury to the nerves themselves such as by mechanical
damage, massive inflammation, and growing tumors.
Visceral Pain
The brain can also register pain from stimuli originating in sensory neurons of
the autonomic nervous system. This so-called visceral pain is not felt in a discrete
location as pain signals transmitted by the sensory-somatic system are.
NSAIDs
Inflammation is caused by tissue damage and, among other things, causes pain.
Damaged tissue releases prostaglandins and these are potent triggers of pain.
Cyclooxygenase 1 (Cox-1)
Cyclooxygenase 2 (Cox-2)
Cyclooxygenase 3 (Cox-3)
Most NSAIDs block the action of all three cyclooxygenases. They include:
aspirin
ibuprofen (Advil®, Motrin®)
naproxen (Aleve®)
and many others
Two NSAIDs
celecoxib (Celebrex®)
rofecoxib (Vioxx®)
were introduced in 1999 that selectively inhibit Cox-2 while leaving Cox-1
untouched. It was hoped that these would provide pain relief without the
gastrointestinal side effects associated with the broad spectrum NSAIDs. However,
the manufacturer of Vioxx® removed it from the market on 30 September 2004
because it increases the risk of heart attacks and strokes.
Acetaminophen (Tylenol®)
Opioids
Some examples:
morphine
codeine
heroin
methadone
oxycodone
Met-enkephalin (Tyr-Gly-Gly-Phe-
Met)
Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)
The drawing shows how this mechanism might work. The activation of enkephalin
synapses suppresses the release of the neurotransmitter (substance P) used by the
sensory neurons involved in the perception of chronic and/or intense pain.
The ability to perceive pain is vital. However, faced with massive, chronic,
intractable pain, it makes sense to have a system that decreases its own sensitivity.
Enkephalin synapses provide this intrinsic pain-suppressing system.
Morphine and the other opioids bind these same receptors. This makes them
excellent pain killers.
The plan: