FENTANYL-RELATED 4-HETEROANILIDO PIPERIDINE OHM3295 AUGMENTS SPLENIC NATURAL-KILLER ACTIVITY AND INDUCES ANALGESIA THROUGH OPIOID RECEPTOR PATHWAYS

Recently, he fentanyl-related compound OHM3295 has been shown to induc e 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) activi ty in a dose-related and naltrexone-reversible manner. The present stu dy investigated the type (delta, kappa or mu) of opioid receptor invol ved in analgesia and immunomodulation after acute administration of OH M3295. CD1 mice pretreated with beta-funaltrexamine (beta-FNA, 40.0 mg /kg) showed an insignificant induction of analgesia (8.4 +/- 3.7%) aft er 3.2 mg/kg OHM3295, whereas mice pretreated with vehicle, norbinalto rphimine (10.0 mg/kg) or naltrindole (20.0 mg/kg) exhibited 43.6 +/- 1 2.6% of maximal analgesia, as determined by the tail-flick latency tes t. Consistent with previous results, acute administration of OHM3295 ( 3.2 mg/kg) augmented splenic NK activity (20.7 +/- 3.4 lytic units [LU ]) relative to vehicle-treated mice (8.2 +/- 0.7 LU). Pretreatment wit h beta-FNA (40.0 mg/kg) completely blocked (9.0 +/- 1.9 LU) OHM3295-me diated augmentation of NK activity, whereas pretreatment with norbinal torphimine (10.0 mg/kg) partially blocked (15.8 +/- 2.2 LU) the drug-i nduced effect. However, pretreatment with naltrindole (20.0 mg/kg) did not antagonize OHM3295-induced increases in splenic NK activity but r ather further enhanced (32.3 +/- 4.2 LU) the effect. NK-enriched effec tor cells from OHM3295-treated mice displayed an increase in conjugati on with YAC-1 target cells, an increase in the percent killing of targ et cells and a significant increase in the number of active killer cel ls 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 vehic le-treated mice after incubation with targets. These results implicate kappa and mu opioid receptor involvement in OHM3295-mediated augmenta tion of splenic NK activity and identify a potential mechanism for thi s enhancement.