Abstract

Repeated exposure to μ-opioid analgesics produces unwanted side effects, including tolerance and physical dependence. δ-Opioid antagonists attenuate development of morphine tolerance and physical dependence. We recently reported that SoRI 9409, a mixed μ-agonist/δ-antagonist, produces antinociception with limited development of tolerance after repeated i.c.v. injections. The current studies report on a more complete characterization of the compound in male ICR mice. SoRI 9409 produced limited antinociceptive effects in the 55°C tail-flick test and full agonist effects in the acetic acid writhing assay after i.c.v. or i.p. administration. Repeated i.p. administration of A₉₀ doses of SoRI 9409 did not produce tolerance. The agonist effects of the compound were preferentially blocked by the μ-selective antagonist β-funaltrexamine. The κ-antagonist nor-binaltorphimine produced partial antagonism, whereas the δ-antagonist naltrindole had no effect on SoRI 9409 antinociception. Intraperitoneal administration of SoRI 9409 preferentially antagonized the antinociceptive actions of the δ-2 agonist [d-Ala²,Glu⁴]deltorphin over the δ-1 agonist cyclic[d-Pen²,d-Pen⁵]-enkephalin and the μ-agonist [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin. SoRI 9409 did not antagonize the antinociceptive effects of the κ-agonist U69,593 (doses up to 60 mg/kg). SoRI 9409 (10 mg/kg i.p.) elicited much less vertical jumping than naloxone (10 mg/kg i.p.) in acute and chronic morphine dependence models. SoRI 9409 also suppressed withdrawal jumping when coadministered with naloxone. These studies indicate that SoRI 9409 acts primarily as a partial μ-agonist/δ-antagonist and supports the hypothesis that this type of compound may have a better therapeutic profile than currently available μ-agonists.