FEATURE pathways. However, this perception depends on the action potential fre-quency, the time interval in between each action potential, and input from higher-order brain centers. The recep-tors responsible for relaying nociceptive information are termed nociceptors. They can be found on the skin, joints, viscera, and muscles. A wide variety of chemical substances activate these re-ceptors, including globulin and protein kinases, arachidonic acid, histamine, nerve growth factor, substance P, calci-tonin gene-related peptide (CGRP), potassium, serotonin, acetylcholine, low-pH solutions, ATP, and lactic acid. Receptors are also activated by temper-produce analgesia in animal models of acute and chronic pain; however, con-cerns remain over dependence, toler-ance, and the cognitive side effects produced by these medications. The undesirable effects of cannabinoids are caused by the global activation of CNS CB1 receptors.3–5 The mechanism is likely multifaceted, involving inhibition of the production and release of proinflammatory and pronociceptive mediators such as reactive oxygen spe-cies and cytokines by peripheral im-mune cells and the peripheral release of endogenous opioids. Since ECs are rapidly degraded, their effects are short-lived, and they are thus unsuitable for have reported effects on the peripheral nervous system, spinal cord mechanisms and supraspinal processes. I would sug-gest that the peripheral mechanisms of spine pain are the point of intersection with the endocannabinoid system. In acute and chronic inflammatory states, spine pain may be modulated by the sensitization and desensitization of no-ciceptors by pro-and anti-inflammatory mediators. SM may produce pain relief by modulating inflammatory processes and sensitization in peripheral tissues. 6 “Pain is the subjective experience one feels because of the activation of these pathways…” ature extremes, high pressures, and tis-sue damage causing inflammation. Nociceptive pathways begin with the transduction of a noxious stimulus, such as mechanical pressure, into action po-tentials by a specialised class of sensory afferent neurones in the periphery (e.g. mechanoreceptors in the skin). Action potentials travel via the axon of the primary afferent neurone, past the cell body located in a dorsal root ganglion, to a synapse in the superficial dorsal horn of the spinal cord. Following the integration of inputs from multiple cell types within the spinal cord, these action potentials will then pass up one of sev-eral ascending pathways to the brain-stem, and subsequently to the thalamus, which then relays the signal to higher brain regions involved in the sensory (e.g. the somatosensory cortex) and emotional/affective (e.g. the amygdala and cingulate cortex) aspects of pain. There is significant crosstalk between supra-spinal nociceptive regions, and nociceptive signals can be amplified or dampened by descending modulatory pathways projecting from the brain to the spinal cord. 3 Systemic administration of cannabi-noid receptor ligands is well known to use as analgesics. However, the recent development of specific inhibitors of the major catabolic enzymes (MAGL and FAAH) has enabled researchers to pro-long the effect of endogenously gener-ated ECs. This is a very promising anal-gesic strategy, since ECs are specifically generated at sites of nociceptive activity, and such an approach may avoid the unwanted effects of global CB1 receptor agonism. 4 MECHANISMS OF PAIN RELIEF BY SPINAL MANIPULATION Spinal manipulation (SM) generally consists in the application of a mechan-ical force on spinal joints in the form of a high velocity and low amplitude thrust preceded by a slower preload phase. Both the preload and thrust phases impact paraspinal muscle responses and load articular tissues, including the in-tervertebral discs, joint capsules, and ligaments. Previous studies suggest that the mechanical force applied during SM alters spinal biomechanics and activates paraspinal sensory terminals. It has been proposed that this afferent fibre stimu-lation initiates a cascade of peripheral and central neurophysiological effects. 6 Previous studies on pain relief by SM Peripheral substance P (SP) is a neuro-transmitter of nociceptive afferent nerves in the somatic nervous system and in synaptic terminals of the spinal dorsal horn. SP effects are mediated through three different neurokinin (NK) receptors: NK-1, NK-2, and NK-3. The NK-1 receptor has a strong affin-ity for SP. SP-induced activation of NK-1 receptors facilitates the processing of noxious information within the spinal cord and is involved in inflammation and neuropathic pain. Transient receptor potential vanilloid subtype 1 (TPRV1) is specifically ex-pressed by the nociceptors of C fibers and has an important role in triggering hyperalgesia by reacting to capsaicin, noxious heat, photons, and various en-dogenous ligands. TRPV1 activity is enhanced by inflammatory mediators such as nerve growth factor, somatosta-tin, bradykinin, prostaglandins, and serotonin, suggesting that TRPV1 is essential for the integration of various signaling pathways that mediate sensi-tivity to stimuli. SP is involved in the hypersensitiza-tion of inflammatory pain by activating NK-1 expressed by nociceptive neurons and potentiating the activity of TRPV1 upon peripheral inflammation. This suggests that the activation of NK-1 receptors by peripheral SP increases TRPV1 sensitivity and triggers hyperal-gesia. 7 Following cervical SM, an increase in plasmatic substance P was reported, while pressure-pain sensitivity de-creased. It was proposed that the aug-mented substance P may underlie the hypoalgesic effects of SM, based on www.Cndoctor.ca PERIPHERAL INFLAMMATION AND SENSITIZATION – SUBSTANCE P AND TRPV1 14 Chiropractic and Naturopathic Doctor July/August 2022
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