BEHAVIORAL CHARACTERIZATION OF THE EXCITATORY AND DESENSITIZING EFFECTS OF INTRAVESICAL CAPSAICIN AND RESINIFERATOXIN IN THE RAT

This study characterized the excitatory (nociceptive) and desensitizin g (antinociceptive) properties of the natural pungent substances, caps aicin (CAP) and resiniferatoxin (RTX) instilled in the bladder (intrav esical, i.ves.) via an indwelling cannula in awake, freely moving rats . The incidence of 9 behaviors was scored for 10 min following i.ves. vehicle or RTX (1.0 nmol). Abdominal licking and head-turning occurred significantly more often in RTX-treated rats compared to vehicle cont rols, whereas head-grooming, locomotion, rearing and biting did not di ffer between the two groups. Little or no vocalization, defecation or hindlimb hyperextension was observed in either RTX- or vehicle-treated rats. A second injection of either vehicle or RTX administered to RTX -treated rats 60 min later did not significantly increase abdominal li cking or head-turning compared to vehicle controls; this subsequent la ck of excitation was taken as a measure of desensitization. In a separ ate experiment, the first injection of i.ves. RTX (0.1-3.0 nmol) incre ased licking in a dose-dependent manner; in contrast, the first inject ion of i.ves. CAP (0.1-3.0 mu mol) significantly increased licking onl y at the intermediate dose tested, 1.0 mu mol. With each subsequent in jection of the same drug and dose at 30-min intervals, licking increas ed to a lesser extent, such that it was not significantry different fr om control after the fourth injection. Rats treated with i.ves. CAP or RTX also did not show increased licking when administered the opposit e treatment 30 min later (RTX or CAP, respectively), indicating cross- desensitization; however, i.ves. administration of a third, higher dos e of RTX reinstated licking behavior in these 'desensitized' rats. Sub cutaneous administration of CAP (18-180 mg/kg) or RTX (18-180 mu g/kg) dose-dependently attenuated the excitatory response to i.ves. CAP and RTX administered 2 days later. Whereas rats treated systemically with RTX also were desensitized to the excitatory effects of RTX instilled in the eye (evaluated in the eye-wipe assay), rats treated i.ves. wit h RTX and vehicle-treated rats showed a normal eye-wiping response. Fi nally, pretreatment with i.ves. ruthenium red, a cation channel blocke r, antagonized the excitatory and desensitizing effects of i.ves. RTX. This study demonstrates that repeated application of both CAP and RTX into the bladder produces behavioral effects indicative of local sens ory afferent desensitization. I.ves. CAP and RTX appear to produce the ir excitatory and desensitizing effects via a common mechanism, which is dependent on cation channel activation. Furthermore, desensitizatio n via i.ves. RTX administration appears to be specific to bladder affe rents, occurs at low doses, and can be achieved over a broad dose rang e with minimal disruption of other behaviors. This study demonstrates for the first time that desensitization of sensory afferents in a deep structure can be produced via local application of RTX in awake, free ly moving animals. Insofar as CAP-sensitive innervation regulates both pain and micturition in the human bladder, the i.ves. model in rats m ay be useful in assessing the utility of local afferent desensitizatio n for the treatment of neuropathic bladder disorders.