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In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence.
J Pharmacol Exp Ther. 2001 May; 297(2):597-605.JP

Abstract

Repeated exposure to mu-opioid analgesics produces unwanted side effects, including tolerance and physical dependence. delta-Opioid antagonists attenuate development of morphine tolerance and physical dependence. We recently 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 antinociceptive 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. Repeated 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 nor-binaltorphimine produced partial antagonism, whereas the delta-antagonist naltrindole had no effect on SoRI 9409 antinociception. Intraperitoneal administration of SoRI 9409 preferentially antagonized the antinociceptive actions of the delta-2 agonist [D-Ala(2),Glu(4)]deltorphin over the delta-1 agonist 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 antinociceptive 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/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 mu-agonist/delta-antagonist and supports the hypothesis that this type of compound may have a better therapeutic profile than currently available mu-agonists.

Authors+Show Affiliations

Department of Biological Sciences, University of Northern Colorado, Greeley, Colorado 80639, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11303048

Citation

Wells, J L., et al. "In Vivo Pharmacological Characterization of SoRI 9409, a Nonpeptidic Opioid Mu-agonist/delta-antagonist That Produces Limited Antinociceptive Tolerance and Attenuates Morphine Physical Dependence." The Journal of Pharmacology and Experimental Therapeutics, vol. 297, no. 2, 2001, pp. 597-605.
Wells JL, Bartlett JL, Ananthan S, et al. In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence. J Pharmacol Exp Ther. 2001;297(2):597-605.
Wells, J. L., Bartlett, J. L., Ananthan, S., & Bilsky, E. J. (2001). In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence. The Journal of Pharmacology and Experimental Therapeutics, 297(2), 597-605.
Wells JL, et al. In Vivo Pharmacological Characterization of SoRI 9409, a Nonpeptidic Opioid Mu-agonist/delta-antagonist That Produces Limited Antinociceptive Tolerance and Attenuates Morphine Physical Dependence. J Pharmacol Exp Ther. 2001;297(2):597-605. PubMed PMID: 11303048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo pharmacological characterization of SoRI 9409, a nonpeptidic opioid mu-agonist/delta-antagonist that produces limited antinociceptive tolerance and attenuates morphine physical dependence. AU - Wells,J L, AU - Bartlett,J L, AU - Ananthan,S, AU - Bilsky,E J, PY - 2001/4/17/pubmed PY - 2001/5/25/medline PY - 2001/4/17/entrez SP - 597 EP - 605 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 297 IS - 2 N2 - Repeated exposure to mu-opioid analgesics produces unwanted side effects, including tolerance and physical dependence. delta-Opioid antagonists attenuate development of morphine tolerance and physical dependence. We recently 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 antinociceptive 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. Repeated 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 nor-binaltorphimine produced partial antagonism, whereas the delta-antagonist naltrindole had no effect on SoRI 9409 antinociception. Intraperitoneal administration of SoRI 9409 preferentially antagonized the antinociceptive actions of the delta-2 agonist [D-Ala(2),Glu(4)]deltorphin over the delta-1 agonist 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 antinociceptive 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/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 mu-agonist/delta-antagonist and supports the hypothesis that this type of compound may have a better therapeutic profile than currently available mu-agonists. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11303048/In_vivo_pharmacological_characterization_of_SoRI_9409_a_nonpeptidic_opioid_mu_agonist/delta_antagonist_that_produces_limited_antinociceptive_tolerance_and_attenuates_morphine_physical_dependence_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11303048 DB - PRIME DP - Unbound Medicine ER -