Rm. Craft et al., BEHAVIORAL CHARACTERIZATION OF THE EXCITATORY AND DESENSITIZING EFFECTS OF INTRAVESICAL CAPSAICIN AND RESINIFERATOXIN IN THE RAT, Pain, 55(2), 1993, pp. 205-215
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.