Behavioral characterization of the excitatory and desensitizing effects of intravesical capsaicin and resiniferatoxin in the rat.
This study characterized the excitatory (nociceptive) and desensitizing (antinociceptive) properties of the natural pungent substances, capsaicin (CAP) and resiniferatoxin (RTX) instilled in the bladder (intravesical, 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 controls, whereas head-grooming, locomotion, rearing and biting did not differ 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 licking or head-turning compared to vehicle controls; this subsequent lack of excitation was taken as a measure of desensitization. In a separate experiment, the first injection of i.ves. RTX (0.1-3.0 nmol) increased licking in a dose-dependent manner; in contrast, the first injection of i.ves. CAP (0.1-3.0 mumol) significantly increased licking only at the intermediate dose tested, 1.0 mumol. With each subsequent injection of the same drug and dose at 30-min intervals, licking increased to a lesser extent, such that it was not significantly different from control after the fourth injection. Rats treated with i.ves. CAP or RTX also did not show increased licking when administered the opposite treatment 30 min later (RTX or CAP, respectively), indicating cross-desensitization; however, i.ves. administration of a third, higher dose of RTX reinstated licking behavior in these 'desensitized' rats. Subcutaneous administration of CAP (18-180 mg/kg) or RTX (18-180 micrograms/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. with RTX and vehicle-treated rats showed a normal eye-wiping response. Finally, pretreatment with i.ves. ruthenium red, a cation channel blocker, 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 sensory afferent desensitization. I.ves. CAP and RTX appear to produce their excitatory and desensitizing effects via a common mechanism, which is dependent on cation channel activation.(ABSTRACT TRUNCATED AT 400 WORDS)
Craft
Rebecca M
RM
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724 USA.
Carlisi
Vincent J
VJ
Mattia
Antonia
A
Herman
Richard M
RM
Porreca
Frank
F
D000283:Administration, Intravesical; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002211:Capsaicin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004224:Diterpenes / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006120:Grooming / Q000187:drug effects; D007279:Injections, Subcutaneous; D007509:Irritants / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology
D004224:Diterpenes; D007509:Irritants; D012430:Ruthenium Red; C024353:resiniferatoxin; D002211:Capsaicin