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 (CCK(B)) receptor antagonist L-365,260 (0.2 mg/kg s.c.) to prevent the development of tolerance to the antinociceptive action of morphine was evaluated by a well-established rat model of unilateral peripheral mononeuropathy. The 4-day pretreatment regimens (saline, L-365,260 or morphine alone, or with the combination of L-365,260 and morphine) were begun on postoperative day 12. The experiments were performed on day 16, when the pain-related behavior reached a stable maximum. Behavioral test based 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 threshold to paw pressure values of the groups pretreated with one of the four regimens were similar, which suggests that the pretreatments had no effect on the development of mechanical allodynia. Pretreatment with morphine 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 to the antinociceptive effect of acute i.v. morphine. The effect of acute morphine in this latter pretreatment group was dose dependent, naloxone reversible and similar to the effect of acute morphine seen in the saline-pretreated group. Our results suggest that in this well-characterized model of neuropathic pain, the development of tolerance to the antinociceptive effect of systemic morphine can be prevented by systemic coadministration of the CCK(B) antagonist L-365,260. We further show, that in contrast to a tonic activity of the endogenous opioidergic system, a tonic activity of the endogenous CCK system cannot be revealed in this rat model of neuropathic pain.