Fentanyl-related 4-heteroanilido piperidine OHM3295 augments splenic natural killer activity and induces analgesia through opioid receptor pathways

M. L. Baker, L. L. Brockunier, J. R. Bagley, C. P. France, D. J.J. Carr

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Recently, the fentanyl-related compound OHM3295 has been shown to induce a naltrexone-sensitive, dose-related analgesia in CD1 mice. However, unlike morphine or fentanyl, which are potent immunosuppressive drugs, OHM3295 has been found to augment splenic natural killer (NK) activity in a dose-related and naltrexone-reversible manner. The present study investigated the type (delta, kappa or mu) of opioid receptor involved in analgesia and immunomodulation after acute administration of OHM3295. CD1 mice pretreated with β-funaltrexamine (β-FNA, 40.0 mg/kg) showed an insignificant induction of analgesia (8.4 ± 3.7%) after 3.2 mg/kg OHM3295, whereas mice pretreated with vehicle, norbinaltorphimine (10.0 mg/kg) or naltrindole (20.0 mg/kg) exhibited 43.6 ± 12.6% of maximal analgesia, as determined by the tail- flick latency test. Consistent with previous results, acute administration of OHM3295 (3.2 mg/kg) augmented splenic NK activity (20.7 ± 3.4 lyric units [LU]) relative to vehicle-treated mice (8.2 ± 0.7 LU). Pretreatment with β- FNA (40.0 mg/kg) completely blocked (9.0 ± 1.9 LU) OHM3295-mediated augmentation of NK activity, whereas pretreatment with norbinaltorphimine (10.0 mg/kg) partially blocked (15.8 ± 2.2 LU) the drug-induced effect. However, pretreatment with naltrindole (20.0 mg/kg) did not antagonize OHM3295-induced increases in splenic NK activity but rather further enhanced (32.3 ± 4.2 LU) the effect. NK-enriched effector cells from OHM3295-treated mice displayed an increase in conjugation with YAC-1 target cells, an increase in the percent killing of target cells and a significant increase in the number of active killer cells compared with NK-enriched effector cells from vehicle-treated mice. In addition, the expression of the early activation antigen CD69 was elevated on NK1.1+ cells from OHM3295-treated mice relative to vehicle-treated mice after incubation with targets. These results implicate kappa and mu opioid receptor involvement in OHM3295- mediated augmentation of splenic NK activity and identify a potential mechanism for this enhancement.

Original languageEnglish (US)
Pages (from-to)1285-1292
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume274
Issue number3
StatePublished - Jan 1 1995
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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