In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence

Repeated exposure to mu -opioid analgesics produces unwanted side effects, including tolerance and physical dependence. delta -Opioid antagonists atte nuate development of morphine tolerance and physical dependence. We recentl y reported that SoRI 9409, a mixed mu -agonist/delta -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 antinocicepti ve effects in the 55 degrees C tail-flick test and full agonist effects in the acetic acid writhing assay after i.c.v. or i.p. administration. Repeate d i.p. administration of A(90) doses of SoRI 9409 did not produce tolerance . The agonist effects of the compound were preferentially blocked by the mu -selective antagonist beta -funaltrexamine. The kappa -antagonist norbinal torphimine produced partial antagonism, whereas the delta -antagonist naltr indole had no effect on SoRI 9409 antinociception. Intraperitoneal administ ration of SoRI 9409 preferentially antagonized the antinociceptive actions of the delta -2 agonist [D-Ala(2),Glu(4)]deltorphin over the delta -1 agoni st cyclic[D-Pen(2),D-Pen(5)]-enkephalin and the mu -agonist [D-Ala(2),N-Me- Phe(4),Gly(5)-ol]-enkephalin. SoRI 9409 did not antagonize the antinocicept ive effects of the kappa -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/k g i.p.) in acute and chronic morphine dependence models. SoRI 9409 also sup pressed withdrawal jumping when coadministered with naloxone. These studies indicate that SoRI 9409 acts primarily as a partial mu -agonist/delta -ant agonist and supports the hypothesis that this type of compound may have a b etter therapeutic profile than currently available mu -agonists.