Sensitization

Nociceptive pathways are subject to sensitization as a consequence of their previous activation. Elucidation of the mechanisms underlying these changes is exceedingly important in achieving an understanding of nociceptive physiology and pathology. Two important terms used in describing these changes are hyperalgesia and allodynia (Fig. 3). Hyperalgesia refers to the increase in perceived intensity of a normally painful stimulus after damage to the stimulated region. Allodynia refers to the pain elicited by a normally innocuous stimulus as a consequence of injury. In terms of sensory pathways, hyperalgesia can be thought of as an increased activation of normally nociceptive pathways, whereas allodynia can be considered as a nociceptive response to the activation of normally nonnociceptive pathways. It is now clear that these sensitization processes involve both peripheral and central mechanisms.

A. Peripheral Sensitization

Peripheral sensitization of nociceptive afferents is measured electrophysiological^ as a reduction in response threshold to a nociceptive stimulus as well as an increased discharge in response to a given

Normal pain threshold

Figure 3 Graphical representation of two components of sensitization. Stimulus-response function before sensitization is shown with the dark dashed line; after sensitization the response increases so that in this example all stimuli elicit the report of pain. Allodynia refers to the painful response to a previously nonpainful stimulus; hyperalgesia refers to the exaggerated response to a normally painful stimulus. The dashed horizontal and vertical lines are provided to give thresholds.

Normal pain threshold

Figure 3 Graphical representation of two components of sensitization. Stimulus-response function before sensitization is shown with the dark dashed line; after sensitization the response increases so that in this example all stimuli elicit the report of pain. Allodynia refers to the painful response to a previously nonpainful stimulus; hyperalgesia refers to the exaggerated response to a normally painful stimulus. The dashed horizontal and vertical lines are provided to give thresholds.

suprathreshold stimulus. Damage to peripheral tissue generally results in sensitization of peripheral nociceptors, although a given stimulus does not sensitize all types of nociceptive responses (e.g., to noxious heat or to high-intensity mechanical stimulation) equally. Similarly, sensitization is not elicited equally well by noxious mechanical and heat stimulation. There are other complications in classifying sensitization responses, e.g., whether it is primary hyperalgesia (sensitization in a region that overlaps the region of injury) or secondary hyperalgesia (sensitization in a region outside the region of primary injury). Primary heat hyperalgesia after a burn injury involves sensiti-zation of the response of nociceptors to noxious thermal stimuli. Primary mechanical hyperalgesia after a burn injury does not involve peripheral sensitization to mechanical stimuli, and so central changes (i.e., central sensitization; see the following section) are believed to be responsible. However, sensitization of the response of mechanical nociceptors does occur and is believed to account for the mechanical hyperalgesia after chemical sensitization. In summary, there is substantial evidence that both thermal and mechanical responses of nociceptors can be sensitized by natural stimuli.

It is now clear that peripheral sensitization after inflammation involves very complex mechanisms in the periphery resulting from the release of numerous substances in the periphery. There are two major sources of these substances. The first of these are peptides such as substance P and/or CGRP released from the nerve terminals themselves due to a local axon reflex and/or impulses elicited in the spinal terminals of the sensory axons and conducted antidromically, the dorsal root reflex. These peptides evoke several effects in the periphery, notably vasodilatation and neuro-genic extravasation (leakage of large molecules from capillaries into the skin). In parallel with these changes is the release into the skin of numerous substances, which have been demonstrated to induce activation and/or sensitization of nocieceptive afferents. These include bradykinin, prostaglandin E2 (PGE2), serotonin, histamine, and nerve growth factor (NGF), each of which is a consequence of a different component of the inflammatory response. Together, this mixture of substances has been referred to as the "inflammatory soup.'' Numerous cell types in the skin such as macrophages, mast cells, and Schwann cells have been shown to be sources of these substances. It has also been demonstrated that certain cytokines such as TNFa and IL-1b are important precursors to the up-regulation of these substances. Expression of so many substances leading to hyperalgesia suggests that it is a highly adaptive response to inflammatory injury, whereby an inflamed limb is protected to promote the healing process.

The mechanism by which these substances sensitize nociceptive afferents is not presently well-defined. In the case of sensitization to noxious heat, there is evidence that some sensitizing agents, e.g., NGF and PGE2, can acutely enhance the response to capsaicin, suggesting a direct effect on the transduction process mediated by the VR1 receptor believed to mediate the response to noxious heat, at least in part. Attention has been focused on second messenger signaling pathways that elicit sensitization or more definitively on antagonists of these pathways that block the sensitization elicited by endogenously released agents (Fig. 4). For example, activation of the adenylyl cyclase/cyclic AMP/PKA intracellular signaling pathway by forsko-lin, a specific activator of this pathway, can result in acute sensitization of the response to PGE2. However, the situation is undoubtedly more complex because activators and inhibitors of another signaling pathway involving the molecule PKC can also affect peripheral sensitization to noxious heat.

TTX-resistant sodium channels are also believed to participate in the peripheral sensitization produced by inflammation. These channels are expressed preferentially in nociceptive afferents and their terminals (see previous discussion), and molecules such as PGE2, bradykinin, serotonin, and NGF that elicit inflammatory hyperalgesia selectively enhance the current produced by these channels via intracellular messengers such as PKA and PKC (Fig. 4). This would be expected to decrease the threshold for activation of nociceptive afferents and increase the discharge in response to a given level of depolarization, because TTX-resistant Na channels have a more rapid recovery from inactivation, rendering them more appropriate for steady discharge than TTX-sensitive channels.

In summary, these studies indicate that peripheral sensitization can involve the action of the sensitizing agents on the transduction process (e.g., via VR1), the cell's excitability, and possibly the spike-encoding process (via the TTX-insensitive Na channel).

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