Pain Mechanisms and Pathways

Pain is a designation for a spectrum of sensations of highly divergent character and intensity ranging from unpleasant to intolerable. Pain stimuli are detected by physiological receptors (sensors, nociceptors) least differentiated morphologically, viz., free nerve endings. The body of the bipolar afferent first-order neuron lies in the dorsal root ganglia. Nociceptive impulses are conducted via unmyelinated (C-fibers, conduction velocity 0.2–2 m/s) and myelinated axons (Aδ-fibers, 10–30 m/s). The free endings of Aδ-fibers respond to intense pressure or heat, those of C-fibers respond to chemical stimuli (H+, K+, histamine, bradykinin, etc.) arising from tissue trauma.

Irrespective of whether chemical, mechanical, or thermal stimuli are involved, they become significantly more effective in the presence of prostaglandins (p.196).

Chemical stimuli also underlie pain secondary to inflammation or ischemia (angina pectoris, myocardial infarction). The intense pain that occurs during overdistension or spasmodic contraction of smooth muscle abdominal organs may be maintained by local anoxemia developing in the area of spasm (visceral pain).

Aδ- and C-fibers enter the spinal cord via the dorsal root, ascend in the dorsolateral funiculus, and then synapse on second-order neurons in the dorsal horn. The axons of the second-order neurons cross the midline and ascend to the brain as the anterolateral pathway or spinothalamic tract. Based on phylogenetic age, a neospinothalamic tract and a palaeospinothalamic tract are distinguished. The second-order (projection) neurons of both tracts lie in different zones (laminae) of the dorsal horn. Lateral thalamic nuclei receiving neospinothalamic input project to circumscribed areas of the postcentral gyrus. Stimuli conveyed via this path are experienced as sharp, clearly localizable pain. The medial thalamic regions receiving palaeospinothalamic input project to the postcentral

gyrus as well as the frontal, limbic cortex and most likely represent the pathway subserving pain of a dull, aching, or burning character, i.e., pain that can be localized only poorly.

Impulse traf c in the neospinothalamic and palaeospinothalamic pathways is subject to modulation by descending projections that originate from the reticular formation and terminate at second-order neurons, at their synapses with first-order neurons or spinal segmental interneurons (descending antinociceptive system). This system can inhibit substance P-mediated impulse transmission from firstto second-order neurons via release of endogenous opiopeptides (enkephalins) or monoamines (norepinephrine, serotonin).

Pain sensation can be influenced or modified as follows:

Elimination of the cause of pain

Lowering of the sensitivity of nociceptors (antipyretic analgesics, local anesthetics)

Interrupting nociceptive conduction in sensory nerves (local anesthetics)

Suppression of transmission of nociceptive impulses in the spinal medulla (opioids)

Inhibition of pain perception (opioids, general anesthetics)

Altering emotional responses to pain, i.e., pain behavior (antidepressants as co-an- algesics)

Eicosanoids

Under the influence of cyclooxygenases (COX-1, COX-2, and their splice variants), the extended molecule of arachidonic acid (eicosatetraenoic acid1) is converted into compounds containing a central ring with two long substituents: prostaglandins, prostacyclin, and thromboxanes. Via the action of a lipoxygenase, arachidonic acid yields leukotrienes, in which ring closure in the center of the molecule (A) does not occur. The products formed from arachidonic acid are inactivated very rapidly; they act as local hormones. The groups of prostaglandins and leukotrienes each comprise a large number of closely related compounds. In the present context, only the most important prostaglandins and their constitutive actions are considered.

Prostaglandin (PG)E2 inhibits gastric acid secretion, increases production of mucus (mucosa-protective action), and elicits bronchoconstriction. PGF2α stimulates uterine motility. PGI2 (prostacyclin) produces vasodilatation and promotes renal excretion of Na+. In addition, prostaglandins synthesized by COX-2 participate in inflammatory processes by sensitizing nociceptors, thus lowering pain threshold; by promoting inflammatory responses by release of mediators such as interleukin-1 and tumor-necrosis factor α; and by evoking fever.

Prostacyclin is produced in vascular endothelium and plays a role in the regulation of blood flow. It elicits vasodilation and prevents aggregation of platelets (functional antagonist of thromboxane).

Thromboxane A2 is a local hormone of platelets; it promotes their aggregation. Small defects in the vascular or capillary wall elicit the formation of thromboxane.

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1 Name derived from Greek eikosi = twenty for the number of carbon atoms and tetra = 4 for the number of double bonds

Leukotrienes2 are produced mainly in leukocytes and mast cells. Newly formed leukotrienes can bind to glutathione. From this complex, glutamine and glycine can be cleaved, resulting in a larger number of local hormones. Leukotrienes are pro-inflamma- tory; they stimulate invasion of leukocytes and enhance their activity. In anaphylactic reactions, they produce vasodilation, increase vascular permeability, and cause vasoconstriction.

Therapeutic uses of synthetic eicosanoids.

Efforts to synthesize stable derivatives of prostaglandins for therapeutic applications have not been very successful to date. Dinoprostone (PGE2), carboprost (15-methyl- PGF2α) and mifeprostone are uterine stimulants (p.130, 254). Misoprostol is meant to afford protection of the gastric mucosa but has pronounced systemic side effects. All these substances lack organ specificity.

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2 Note the change in chemical nomenclature: - triene (tri=three), although leukotrienes possess four double bonds; however, of these only the conjugated ones are counted