a significant effect on reducing participants’ reported pain severity and intensity. However, the studies in the field of nutrition and chronic pain, including those included in the meta-analysis, were of low quality, and there is insufficient
evidence to make specific dietary recommendations. More rigorous studies examining nutrition with chronic pain as a primary outcome are needed to determine the role of nutrition in chronic pain (Lara-Palomo et al., 2022).
NOCICEPTORS AS SENSORS OF THE PAIN PATHWAY
Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. For decades, attempts have been made to study and classify these specialized sensory neurons. Although we are far from understanding the cell biology of pain perception. Significant insights into the cellular and molecular basis of cutaneous nociception have been realized from studies on conscious humans and surrogate animal models. To a considerable extent, these advances are hampered by the difficulties inherent in studying neuronal processes in humans: cellular changes in nociceptors induced by invasive methods, the inability to record directly from the tiny structures where transduction of noxious stimuli occurs, and the uncertainty in model systems that an animal’s behavior is due to its perception of pain. However, cutaneous nociceptors have been significantly studied in their role in pain conduction, modulation, and transmission. Cutaneous nociceptors are an extremely heterogeneous group of neurons housed in peripheral sensory ganglia located just outside the central nervous system (CNS) that transduce external noxious stimuli in the skin, up to meters away from their cell bodies. Minimally invasive extracellular single-unit recordings from nerve fibers in peripheral nerves (microneurography) and skin-nerve preparations in mammals and microneurography combined with psychophysical measurements in human subjects have revealed the existence of distinct classes of nociceptor activated by noxious stimuli. Adequate stimuli include temperature extremes (> ~40°C–45°C or < ~15°C), intense pressure, and chemicals signaling potential or actual tissue damage. Nociceptors are generally electrically silent and transmit all-or-none action potentials only when stimulated. However, nociceptor activity does not per se lead to the perception of pain. The latter requires peripheral information to reach higher centers and normally depends on the frequency of action potentials in primary afferents, temporal summation of pre-and postsynaptic signals, and central influences (Roza & Bernal, 2022). The speed of stimuli transmission is reportedly correlated to the diameter of axons of sensory neurons and whether or not they are myelinated. Most nociceptors have small diameter unmyelinated axons (C-fibers) bundled in fascicles surrounded by Schwann cells and support conduction velocities of 0.4–1.4 m/s. Initial fast-onset pain is mediated by A-fiber nociceptors whose axons are myelinated and support conduction velocities of approximately 5–30 m/s (most in the slower A δ range). Nociceptive fibers have been classified based on their conduction velocity and sensitivity and threshold to noxious mechanical (M), heat (H), and cold (C). Units responding to thermal, mechanical, and chemical stimuli (polymodal) are the most common C-fiber type observed in fiber recordings (C-MH, C-MC, C-MHC). See Figure 2.
Figure 2: Anatomy of Nociceptors
From: Khendroud et al., 2022. ©2010 American Society for Clinical Investigation. Recreated under the Creative Commons Attribution License (CC BY 4.0). C-fibers responsive to noxious heat (C-H; ~10% of C-nociceptors) play a key role in heat sensation. A-fiber nociceptors are predominately heat- and or mechanosensitive (A-MH, A-H, A-M); however, sensitivity to noxious cold is also observed. Determining the contribution of each of these fiber types to pain perception requires an understanding of the molecular mechanisms underlying the detection of particular stimulus modalities and nociceptor connectivity in central circuits. Noxious stimuli are transduced into electrical signals in free “unencapsulated” nerve endings that have branched from the main axon and terminate in the wall of arterioles and surrounding connective tissue and may innervate distinct regions in the dermis and epidermis. The endings are ensheathed by Schwann cells except at the end bulb and mitochondria- and vesicle-rich varicosities. Fibers lose their myelin sheath, and the unmyelinated A-fiber branches cluster in separated small spots within a small area, the anatomical substrate for their receptive field. C-fiber branches are generally more broadly distributed, precluding precise localization of the stimulus. In contrast, specialized nonneuronal structures conferring high sensitivity to light touch, stretch, vibration, and hair movement are innervated by low threshold A-fibers (Neto et al., 2022). Nociceptive endings are in the vicinity of keratinocytes, mast cells, and Langerhans cells, indicating the capacity of peripheral sensory endings to monitor the status of the skin. Nociceptors, like other primary somatosensory neurons, are pseudounipolar: A single
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