In an effort to identify mechanisms underlying hyperalgesia and allodynia observed in the presence of injury and disease, scientists have studied mechanisms underlying both ascending and descending pathways. As described above, the first step in the ascending pathway is stimulus transduction. Single-unit recording of nociceptive afferents indicates that peripheral terminals are sensitized in the presence of injury or inflammation (13). There are at least three mechanisms that could account for the observed increase in excitability. The first is a change in tissue properties, such that stimuli are conveyed to afferent terminals more readily. Analysis of changes in tissue mechanics observed in the presence of inflammation suggests that changes in tissue properties may contribute to nociceptor sensitization (58).
A second mechanism that may account for the sensitization of nociceptor terminals is a change in the transduction process. In the case of visceral structures, such as the bladder or colon, where release of ATP appears to contribute to stimulus transduction, an increase in the release of ATP would contribute to an apparent increase in the excitability of nociceptive terminals. As indicated above, following inflammation of the colon (47) and bladder (59), an increase in evoked release of ATP has been observed. Alternatively, there may be changes in the properties of protein/protein complexes underlying stimulus transduction. Again, as mentioned above, inflammation results in an increase in the magnitude of ATP-evoked currents in sensory neurons (48,49). Thus, even if there were no changes in ATP release, an increase in the sensitivity of ATP receptors would contribute to nociceptor sensitization. Inflammation-induced changes in the properties of other transducers, such as those underlying changes in pH (60), receptors for inflammatory mediators such as bradykinin (61), and receptors for neurotrophins such as brain-derived neurotrophic factor (62-64), have also been described.
TRPV1, a transducer for noxious heat (36), protons (36) and the activation of intracellular signaling cascades (65), is one of the most thoroughly characterized transducers. Inflammation results in several changes in the expression and biophysical properties of TRPV1, which all enable this channel to play a critical role in inflammatory hyperalgesia. There is an increase in channel density that appears to reflect in increase protein translation (66). The desensitiza-tion of the channel appears to be significantly attenuated (67), enabling the channel to more readily contribute to repeated nociceptor activation. The channel itself may also be sensitized, such that temperature threshold for channel activation is significantly lowered (68). Importantly, there is evidence that the threshold for channel activation may be lowered to approximately 37°C, a threshold that would mean the channel could be activated at resting body temperatures. This observation has led to the suggestion that TRPV1 may mediate ongoing pain associated with inflammation (69). Inflammation-induced changes in TRPV1 illustrate the multiplicity of ways in which changes in transducers and/or their properties may contribute to the sensitization of nociceptive afferents.
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