Peripheral Mediators of Colorectal Nociception and Sensitization

[摘要] Several ion channels are thought to facilitate colorectal afferent neuron sensitization, which contributes to abdominal pain in irritable bowel syndrome (IBS). In the present work, I hypothesized that two such channels – TRPV1 and P2X3 – cooperate to mediate colorectal pain and hypersensitivity. To test this, I employed TRPV1-P2X3 double knockout (TPDKO) mice and pharmacological antagonists and evaluated combined channel contributions to whole- organism responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of afferent mechano-sensitive and -insensitive classes were not different in TPDKO mice. Whereas responses of mucosal and serosal class afferents to mechanical probing were unaffected, responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice as was sensitization by inflammatory soup of both muscular and muscular/mucosal afferents. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated afferent responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that: (1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally and (2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than single antagonism. The relative importance of these channels appears to be enhanced in hypersensitivity, highlighting the potential utility of multi-target pharmacotherapy in IBS.

[发布机构] the University of Pittsburgh