Pathophysiology of Pain

Enormous strides have been made in understanding the neurophysiology and neurochemistry of the systems that transmit and modulate information about noxious events.^7,8 Much also is known about acute inflammation, which commonly drives these neural processes. In contrast, relatively little is known about the pathophysiology underlying most persistent pain syndromes. Nonetheless, it is now widely accepted that persistent pain may be sustained by different types of mechanisms and experts agree that clinical characteristics can be used to broadly divide pain syndromes into nociceptive, neuropathic, psychogenic, mixed, or idiopathic. Although this classification is clearly an oversimplification, it has been found useful in assessment and therapeutic decision making.

Nociceptive Pain and Its Mechanisms

Clinically, pain can be labeled “nociceptive” if it is inferred that the pain is due to ongoing activation of the nociceptive system by tissue injury. Although neuroplastic changes (such as those underlying tissue sensitization) are clearly involved, nociceptive pain is presumed to occur as a result of the normal activation of the sensory system by noxious stimuli, a process that involves transduction, transmission, modulation and perception.

Tissue injury activates primary afferent neurons called nociceptors, which are small diameter afferent neurons (with A-delta and C-fibers) that respond to noxious stimuli and are found in skin, muscle, joints, and some visceral tissues.⁷ These fibers have specific receptors that may be responsible for noxious mechanical, chemical or thermal stimuli. One class, called transient receptor potential (TRP) receptors, has been undergoing intensive investigation in the hope of ultimately yielding new therapies for pain.⁹ The TRPV1 receptor, for example, has been found to be the specific site for reaction to capsaicin, a compound that activates C-fiber nociceptors. Presumably, nociceptive processes linked to noxious events involving somatic or visceral structures begin with activation of these specific receptors, which leads to transduction, the process by which exposure to a sufficient stimulus produces depolarization of the peripheral nerve.

Nociceptive primary afferent neurons are varied. Most are “silent”, active only when suprathreshold stimuli impinge. Some are specific to one type of stimulus, such as mechanical or thermal, but most are polymodal. The number and size of the receptive fields served by each fiber may be small or large, respectively. The meaning of this variability in terms of physiology or disease is not yet known, and research linking different types of nociceptors to disease states, or potential therapeutic targets, is still rudimentary.