In Vivo Pharmacological Characterization of SoRl 9409,a Nonpeptidic Opioid #mu#-Agonist/#delta#-Antagonist That Produces Limited Antinociceptive Tolerance and Attenuates Morphine Physical Dependence

摘要

Repeated exposure to fL-opioid analgesics produces unwanted side effects, including tolerance and physical dependence. 8-0pioid antagonists attenuate development of morphine tol- erance and physical dependence. We recently reported that SoRI 9409, a mixed fL-agonist/8-antagonist, produces antino- ciception 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-tlick test and full agonist effects in the acetic acid writhing assay after i.c.v. or i.p. administration. Repeated i.p. administration of Ago doses of SoRI 9409 did not produce tolerance. The agonist effects of the compound were preferentially blocked by the J.L-selective antagonist {3-funaltrexamine. The K-antagonist nor- binaltorphimine produced partial antagonism, whereas the o-antagonist naltrindole had no effect on SoRI 9409 antinoci- ception. Intraperitoneal administration of SoRI 9409 preferen- tially antagonized the antinociceptive actions of the 0-2 agonist [D-Ala2,Glu4]deltorphin over the 0-1 agonist cyclic[D-Pen2,D- Pen5]-enkephalin and the JJ,-agonist [D-Ala2,N-Me-Phe4,Gly5- ol]-enkephalin. SoRI 9409 did not antagonize the antinocicep- tive effects of the K-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 JJ,-agonistlo- antagonist and supports the hypothesis that this type of com- pound may have a better therapeutic profile than currently available #mu#-agonists.