Nociception provides a means of neural feedback that allows the central nervous system (CNS) to detect and avoid noxious and potentially damaging stimuli in both active and passive settings. The sensation of pain divides into four large types: acute pain, nociceptive pain, chronic pain, and neuropathic pain. This article will consider the categories of acute and nociceptive pain together. Acute noxious stimuli (e.g., heat, cold, mechanical force, or chemical stimulation) trigger nociceptors. Acute pain becomes inflammatory pain when the noxious stimulus persists long enough to allow nociceptive neurons to release their pro-inflammatory markers and sensitize or activate responsive cells in their local environment. Nociceptive pain arises from tissues damaged by physical or chemical agents such as trauma, surgery, or chemical burns, while neuropathic pain arises from diseases or damage mediated directly to sensory nerves, such as diabetic neuropathy, shingles, or postherpetic neuralgia. Differentiating acute and nociceptive pain from neuropathic pain aids in understanding the broader study of pain; however, neuropathic pain will not be evaluated further in this article.
Regarding active settings, stimulated nociceptive neurons convey high-threshold noxious stimuli to the CNS. The nociceptive signal may either get redirected immediately in a spinal reflex loop, producing a rapid and reflexive withdrawal or transported to the areas of the brain responsible for integrating the information with higher-ordered sensations such as pain. In addition to spinal afferent transmission to the CNS, nociceptive neurons are also capable of responding to noxious stimuli by secreting chemical signals from their peripheral nerve endings. Local actions on nearby neuronal and non-neural cells undergo mediation through the release of vesicles containing preformed pro-inflammatory cytokines and growth factors.
Depending on the specific monomodal sensitivity of a previously inactive nociceptor, specific noxious stimuli are detected by expressed receptors that open their cation channels in response to activation. The open cation channels on the nociceptive neurons depolarize the nociceptor, inducing vesicle fusion and cytokine release. The cytokines are pro-inflammatory, and once released, they elicit and propagate a matched release of pro-inflammatory cytokines from local epithelial, endothelial, and lymphoid cells. The responding cells may then migrate or otherwise disseminate their pro-inflammatory signals that go on to sensitize or activate surrounding nociceptors originally outside of the primary nociceptive field.
The spread of nociceptor-induced inflammation occurring over an area greater than that of the original nociceptor(s) involved is referred to as neuroinflammation. The propagation from nociceptive neurons to the surrounding cells, which may in-turn sensitize nearby nociceptive neurons, is why neuroinflammation is considered to be a self-reinforcing phenomenon. Not only do the released pro-inflammatory molecules activate local inflammatory cells, but they are also capable of directly activating other nociceptive nerve endings because almost all nociceptive nerve endings possess receptors for all of the pro-inflammatory markers they are capable of releasing. The pro-inflammatory molecules released from a directly stimulated nociceptive neuron are capable of binding to and activating a local nociceptive neuron entirely unaffected by the original stimulus. As with direct activation, the pro-inflammatory molecules bind the receptors on nociceptive nerve endings and depolarize the cell. Depolarization induces mitogen and protein activated kinases that phosphorylate other transducer proteins, such as TRPV1. This will activate and reinforce the depolarization, which, if of sufficient amplitude, will recruit voltage-gated sodium channels and truly depolarize the nerve fiber.
Nociceptive signals cease with the termination of the stimulus, dephosphorylation, and suppression of the receptor, or once the influx of calcium through the open membrane proteins induces the nociceptive nerve ending to collapse and become refractory to restimulation in either neuronal or secretory mechanisms. The collapse of the nociceptor following stimulation supports the finding that noxious stimuli quickly adjust, and their conscious perception abates quickly once their peripheral activity ceases.
There is also a mostly unexplored role of passive nociception. Passive nociception refers to the involvement of inactive nociceptors, by their presence and previous activations, in guiding conscious actions so that the individual performs them in a manner least likely to produce pain or injury. Inactive nociceptors may provide less-than conscious "nudges" that strongly encourage the avoidance of potentially injurious and hazardous exposures. Baliki and Apkarian presented this explanation and differentiated the subconscious, unconscious, or preconscious processes through which nociception may guide behaviors from those more active processes that steer actions through the conscious and subjective experience of pain. Their results demonstrate the effects that an absence of nociceptive input may have in three poignant studies; the general disregard for injury seen in patients with painless channelopathies, the self-destructive gait seen in patients rendered insensitive to pain due to leprosy, and the boney destruction of weight-bearing joints seen in patients with painless Charcot joints of tabes dorsalis. They postulate that the act of walking with proper gait, sitting with proper posture, or standing and stretching at regular intervals during long sedentary periods spent studying, are unconsciously motivated by nociceptive signals. These studies illustrate the various injuries that are possible in the absence of the protective nociceptive signals that protect the body from avoidable joint injuries, muscle spasms, or pressure ulcers that would otherwise be difficult to imagine in an unafflicted individual capable of perceiving and avoiding these injuries.
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