PREVENTION OF TOLERANCE TO THE ANTINOCICEPTIVE EFFECTS OF SYSTEMIC MORPHINE BY A SELECTIVE CHOLECYSTOKININ-B RECEPTOR ANTAGONIST IN A RAT MODEL OF PERIPHERAL NEUROPATHY

The ability of pretreatment by the selective cholecystokinin-B (CCKB) receptor antagonist L-365,260 (0.2 mg/kg s.c.) to prevent the developm ent of tolerance to the antinociceptive action of morphine was evaluat ed by a well-established rat model of unilateral peripheral mononeurop athy. The 4-day pretreatment regimens (saline, L-365,260 or morphine a lone, or with the combination of L-365,260 and morphine) were begun on post-operative day 12. The experiments were performed on day 16, when the pain-related behavior reached a stable maximum. Behavioral test b ased on a mechanical stimulus (vocalization threshold to paw pressure) and relatively low acute doses of systemic morphine (0.1, 0.3 and 1.0 mg/kg i.v.) were used. On day 16, the base-line vocalization threshol d to paw pressure values of the groups pretreated with one of the four regimens were similar, which suggests that the pretreatments had no e ffect on the development of mechanical allodynia. Pretreatment with mo rphine alone (10 mg/kg s.c., two times a day during 4 days) induced a complete tolerance to the antinociceptive effect of acute morphine (0. 1-1.0 mg/kg i.v.). However, pretreatment with the combination of L-365 ,260 with morphine completely prevented the development of tolerance t o the antinociceptive effect of acute i.v. morphine. The effect of acu te morphine in this latter pretreatment group was dose dependent, nalo xone reversible and similar to the effect of acute morphine seen in th e saline-pretreated group. Our results suggest that in this well-chara cterized model of neuropathic pain, the development of tolerance to th e antinociceptive effect of systemic morphine can be prevented by syst emic coadministration of the CCKB antagonist L-365,260. We further sho w, that in contrast to a tonic activity of the endogenous opioidergic system, a tonic activity of the endogenous CCK system cannot be reveal ed in this rat model of neuropathic pain.