Chapter 2 Neurochemistry of Somatosensory and Pain Processing

Question 1

What are the mediators of “inflammatory soup” ?

Answer 1

Bradykinin, Low pH, Serotonin, Histamine, Eicosanoids (the prostaglandins, thromboxanes, and leukotrienes.), Nitric Oxide, Adenosine, Cytokines,

Question 2

What is Bradykinin?

Answer 2

a potent vasodilating peptide, plays a critical
role in inflammatory pain and hyperalgesia via actions on two G-protein–coupled receptors: the constitutively expressed B2 receptor, and the B1 receptor, the expression of which is increased following tissue injury

Question 3

How does Low pH (Excess free H) contributes to the pain and hyperalgesia?

Answer 3

Low pH selectively causes activation and sensitization of nociceptors to mechanical stimuli by opening dorsal root ganglion neuron specific acid-sensing ion channels

Question 4

How is Serotonin released?

Answer 4

Serotonin is released from platelets in response to platelet activating factor derived from mast cell degranulation, leads to pain by directly activating nociceptors. Serotonin also potentiates bradykinin induced pain and nociceptor activation.

Question 5

How is Histamine released?

Answer 5

Histamine is released from mast cells by Substance P and calcitonin gene–related peptide (CGRP). These neuropeptides are derived from activated nociceptors and produce a variety of responses, including vasodilation and edema.
histamine excites polymodal visceral nociceptors and potentiates the responses of nociceptors to bradykinin and heat.

Question 6

What are Eicosanoids?

Answer 6

Eicosanoids are a large family of arachidonic acid metabolites that include the prostaglandins, thromboxanes, and leukotrienes.

Question 7

How do Prostaglandins work?

Answer 7

Prostaglandins, synthesized by the constitutive enzyme, COX-1, and by the inducible enzyme COX-2,13 reduce the activation threshold of tetrodotoxin-resistant Na1 currents in nociceptors, increase intracellular cAMP levels, and increase the excitability of sensory neurons

Question 8

How do Leukotrienes work?

Answer 8

Leukotrienes, metabolites of the lipoxygenase pathway, are released by macrophages and mast cells, contribute to hyperalgesia and sensitization to mechanical stimuli by acting on G-protein–coupled receptors (GPCR) and by serving as chemoattractants for cytokine-producing cells,
and result in further sensitization of primary afferents.

Question 9

How does Nitric Oxide work?

Answer 9

Nitric oxide (NO) released by damaged afferents and acting on soluble guanylyl cyclase (sGC) can further sensitize nearby neurons, augmenting pain and inflammation in both GPCR and non–GPCR-mediated pathways.

Question 10

What is the role of Adenosine?

Answer 10

Adenosine and its mono- and poly-phosphate derivates (AMP, ADP, ATP) are increased in the extracellular space with tissue injury and inflammation.
Adenosine induces pain in humans by direct activation of nociceptors. ATP also induces pain in
humans and activates C-nociceptors in healthy human skin, but does not sensitize C fibers to mechanical or heat stimuli. It is thought that ATP activates nociceptive neurons in normal skin via the purinergic receptors P2X3 and the heteromeric P2X2/P2X3 receptor

Question 11

What are Cytokines?

Answer 11

Cytokines (e.g., interleukin-1b (IL-1b); tumor necrosis factor a (TNFa); interleukin-6 (IL-6)) are released by a variety of cells, such as macrophages, astrocytes, and Schwann cells, to regulate inflammatory cell responses, but also promote pain signaling.
Both IL-1b and TNFa directly excite and sensitize nociceptive afferent fibers to thermal and mechanical stimuli
IL-6 in combination with its soluble IL-6 receptor also sensitizes nociceptors to heat.

Question 12

How does Nerve growth factor (NGF) may contribute to inflammatory pain ?

Answer 12

Nerve growth factor (NGF) may contribute to inflammatory pain via direct and indirect mechanisms. Inflammatory mediators, such as cytokines, increase NGF production in inflamed tissues. In turn, NGF stimulates mast cells to release histamine and serotonin, which can sensitize primary afferent fibers. Further, NGF itself
may directly sensitize nociceptors and can alter the distribution of A-d fibers such that a greater proportion of fibers have nociceptor properties. Heat hyperalgesia can be induced by NGF acting directly on the peripheral terminals of primary afferent fibers.

Question 13

What are the numerous mediators released into inflamed or injured tissue that act to limit pain transmission?

Answer 13

Opioids, Acetylcholine, Gamma amino butyric acid (GABA), Somatostatin (SST)

Question 14

How do Gamma amino butyric acid (GABA) work?

Answer 14

Gamma amino butyric acid (GABA) may have a peripheral role in pain transmission similar to the bimodal actions of acetylcholine.
GABAA receptors are located on unmyelinated
primary afferents and activation of these receptors by low doses of the agonist muscimol decrease pain, whereas high doses potentiate pain.

GABAA receptors have also been found in DRG cells and on their central terminals in the dorsal horn, and direct application of GABA antagonists
to DRG cells decrease hypersensitivity in an animal model of neuropathic pain

Question 15

How is the NMDA receptor activated?

Answer 15

The NMDA receptor is recruited only by intense
and/or prolonged somatosensory stimuli that are sufficient to relieve the tonic magnesium block that regulates its divalent cation channel. Persistent activation of NMDA receptors leads to sensitization of dorsal horn neurons that includes an increase in receptive field size, decreased activation threshold, and prolonged depolarization.

Question 16

Multiple factors influence NMDA receptor–related sensitization. What is the effect of Bradykinin on the receptor?

Answer 16

the release of bradykinin leads to increases
in spinal glutamate released by astrocytes and
neurons. This glutamate activates NMDA receptors,
augmenting central sensitization.

Question 17

What are the inhibitory neurotransmitters in the somatosensory system?

Answer 17

The amino acids glycine and gamma-amino-butyric acid (GABA) are the chief inhibitory neurotransmitters in the somatosensory system.
Glycine is the chief inhibitory amino acid at spinal levels while GABA predominates at higher levels.

Question 18

Where are the receptor sites for Glycine and GABA?

Answer 18

Two receptor sites for glycine, a chloride-linked, strychninesensitive receptor and a strychnine-insensitive regulatory site on the NMDA glutamate receptors. GABA is found in
local circuit neurons of spinal laminae I, II, and III.

Question 19

What are the three types of GABA receptors identified?

Answer 19

GABA-A receptor is linked to a chloride channel and modulated by barbiturates, benzodiazepines and alcohol. Selective GABAA agonists include muscimol and selective antagonists include gabazine.

GABA-B receptor has been associated with both a potassium ionophore and with a G-protein–linked complex. Baclofen is a selective GABAB receptor agonist and phaclofen is a selective antagonist.

GABA-C receptor has also been described as associated with a potassium channel ionophore.Cis-4-aminocrotonic acid (CACA)
is a selective agonist for this site, but there is no selective antagonist for GABAC receptors.present. GABAC receptors do not appear to have any role in the modulation of somatosensory information.

Question 20

What is the role of Norepinephrine in somatosensory transmission?

Answer 20

Norepinephrine is another abundant inhibitory neurotransmitter, and is especially important in descending brainstem projections to the dorsal horn. The inhibitory effects of norepinephrine in the spinal cord appear to be twofold by directly activating inhibitory GABAergic interneurons and by also inhibiting excitatory interneurons.The adrenergic receptors include two broad classes
termed the alpha- and beta-receptors, each of which in turn have several subtypes. The a2-adrenergic receptor is the primary form found in the spinal dorsal horn that has an inhibitory role on the processing of sensory information.

Question 21

What is the role of Serotonin in somatosensory transmission?

Answer 21

Serotonin is also involved in descending pathways to the spinal dorsal horn, predominantly from the midbrain raphe nuclei. There are multiple serotonin receptor subtypes including 5HT-1, 2, and 3 receptors
Currently, it is thought that the antinociceptive effects are mediated by activation of a-1
adenoreceptors and 5HT2 receptors leading to descending inhibition.

Question 22

What is the role of Adenosine in somatosensory transmission?

Answer 22

Adenosine is another important inhibitory neurotransmitter at spinal levels.
There are at least two types of adenosine
receptors termed the A1 and A2 sites. Occupation of these sites by adenosine results in G-protein–mediated alterations of cyclic AMP levels in target cells. Adenosine may mediate a portion of the analgesia produced by brainstem norepinephrine projections to the spinal cord and appears to have especially robust analgesic properties in neuropathic pain conditions.

Question 23

What is the role of Acetylcholine in somatosensory transmission?

Answer 23

Acetylcholine (Ach) is yet another neurotransmitter that mediates antinociception at the level of the spinal dorsal horn. Stimulation of the vagus nerve results in inhibition of pain transmission, and it is likely that this effect is mediated by Ach. Ach may also contribute to the analgesia produced by the a2-adrenergic receptor agonist clonidine.
The antinociceptive effects of acetylcholine appear mediated by the muscarinic and not by the nicotinic acetylcholine receptor subtypes.

Question 24

What are the excitatory neuropeptides in the somatosensory system?

Answer 24

Substance P and neurokinin A serve as excitatory neuropeptides in the somatosensory system. The receptors for these peptides include the neurokinin 1 and 2 sites, each of which have been associated with elevation of intracellular calcium levels, perhaps through liberation of inositol phosphate.

Question 25

Where are the excitatory neuropeptides in the somatosensory system located?

Answer 25

These two peptides may be present in intrinsic neurons of the spinal dorsal horn and thalamus
but are especially concentrated in primary afferent
fibers. At the spinal level, these peptides are only released following application of noxious stimuli which are sufficient to produce sustained discharges in C-nociceptors, although some small myelinated (Ad) fibers may also contain substance P.

Question 26

What causes increase in release of substance P?

Answer 26

CGRP like substance P synthesis and release are increased by another excitatory peptide, neuropeptide Y. Spinal release of CGRP has an excitatory effect on wide dynamic range neurons,

Question 27

What are the four ion channels involved in pain

signal propagation in the CNS?

Answer 27

Sodium, Calcium, Potassium, and Chloride.

Question 28

What is the role of Na channels in pain

signal propagation in the CNS?

Answer 28

Sodium channels serve as the key to propagation of neural impulses throughout the nervous system, as the opening of these channels is the primary event underlying the depolarization of nerve membranes.
The local anesthetics lidocaine and bupivacaine physically block sodium channels, preventing the movement of sodium across the membrane.

Question 29

What is the role of K channels in pain

signal propagation in the CNS?

Answer 29

Potassium is the second main cation of the neuronal action potential.Opening of voltage-gated potassium channels allows outward positive current flow from neurons, such as during repolarization following an action potential. Blockade of
these channels initially prolongs generation of action potentials.
Continued application, however, prevents repolarization and so ultimately produces a failure to generate action potentials. The inwardly rectifying channels establish and regulate the resting membrane potential.