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.
Footnotes
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Send reprint requests to: Edward Bilsky, Ph.D., Department of Biological Sciences, University of Northern Colorado, Greeley, CO 80639. E-mail: ejbilsk{at}bentley.unco.edu
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This investigation was partially supported by the National Institute on Drug Abuse (Grant DA08883), a Faculty and Research Publications Board grant from the University of Northern Colorado, Greeley, CO, and a grant-in-aid of research from Sigma Xi.
- Abbreviations:
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- U69,593
- (5α,7α,8β)-(+)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)-benzeneacetamide
- β-FNA
- β-funaltrexamine
- nor-BNI
- nor-binaltorphimine
- DPDPE
- cyclic[d-Pen2,d-Pen5]-enkephalin
- ANOVA
- analysis of variance
- NTB
- naltriben
- Received April 26, 2000.
- Accepted December 29, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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