~) Pergamon Int. J. Immunopharmac., Vol. 16, No. 10, pp. 835-844, 1994 Elsevier Science Ltd Copyright © 1994 International Society for Immunopharmacology Printed in Great Britain. All rights reserved 0192- 0561/94 $7.00 + .00 0192 - 0561(94)00046-8 OHM3295: A FENTANYL-RELATED 4-HETEROANILIDO PIPERIDINE WITH ANALGESIC EFFECTS BUT NOT SUPPRESSIVE EFFECTS ON SPLENIC NK ACTIVITY IN MICE DANIEL J. J. CARR,* MARC L. BAKER,* CHARLES HOLMES, t LINDA L. BROCKUNIER, t JEROME R. BAGLEY ~ and CHARLES P. FRANCE t Departments of *Microbiology, Immunology, Parasitology, and *Pharmacology, LSU Neuroscience Center, Louisiana State University Medical Center, New Orleans, LA, 70112-1393, U.S.A.; and *Ohmeda Inc., Murray Hill, New Jersey, U.S.A. (Received 14 February 1994 and in final forrn 13 May 1994) Abstract -- The immunoregulatory effects of fentanyl and a fentanyl-related compound, OHM3295, were studied in mice. Male CD1 mice treated with a range of fentanyl doses (0.1 - 1.0 mg/kg, subcutaneously) showed suppression of splenic natural killer (NK) activity following 0.25 - 0.50 mg/kg fentanyl dose but not higher (0.75-1.0 mg/kg) or lower (0.1 mg/kg) doses. Fentanyl (0.01-32.0 mg/kg) also induced dose- related analgesia as measured by an increase in tail flick latency; these analgesic effects were antagonized by naltrexone (1.0-10.0 mg/kg). Pretreatment with naltrexone (1.0-3.2 mg/kg) resulted in significant suppression of splenic NK activity following fentanyl (10.0 - 32.0 mg/kg) administration. In comparison to fentanyl, OHM3~95 (3.2-25.0 mg/kg) augmented splenic NK activity in a naltrexone-reversible manner. Similar to fentan3~l, OHM3295 (1.0- 32.0 mg/kg) also induced a naltrexone-sensitive, dose-related analgesia as measured by an increase in tail flick latency. These results with OHM3295 demonstrate a novel profile of effects which includes naltrexone-sensitive analgesic effects in the absence of immunosuppressive effects. In addition, this is the first reported case in which a compound with opioid analgesic effects has been shown to potentiate natural killer cytolytic activity following in vivo administration. Morphine is a commonly used analgesic to control acute and chronic pain; however, morphine and heroin are potent immunosuppressive drugs in rodents (Shavit etal., 1984; Bryant et al., 1987; Pruett et al., 1992; Pacifici et aL, 1992; Bussiere et aL, 1993; Freier & Fuchs, 1993), swine (Molitar et al., 1992), non-human primates (Liu et aL, 1992; Carr & France, 1993), and humans (Donahoe et aL, 1985; Novick etaL, 1989; Klimas etal., 1991). Moreover, one manifestation of the immunosuppres- sive effects of opioids in vivo is a diminished resistance to bacterial (Tubaro et al., 1983) and viral (Dismukes et al., 1986; Lorenzo et al., 1987) infections. Recently, the fentanyl derivative OHM3295 has been shown to have opioid and non-opioid effects which appear to be species specific. For example, OHM3295 has been shown to displace 3H-naloxone from/a-opioid binding sites in rat brain membranes (Kd of 8.4 nM), to have analgesic effects in the mouse hot-plate assay, and to reverse morphine- induced respiratory depression in rabbits (Bagley et al., 1991). In addition, OHM3295 can be substi- tuted for naltrexone in drug discrimination tasks in rhesus monkeys (France et al., 1994). However, in monkeys the analgesic effects of OHM3295 are not antagonized by naltrexone (France et al., 1994). These opioid-like and non-opioid-like effects of OHM3295 suggested that a further comparison of this compound to typical /a-opioids might yield additional novel effects. In the present study, the immunoregulatory effects of OHM3295 and fentanyl on splenic natural killer (NK) activity were assessed concurrently with analgesic effects of these com- pounds using the tail flick assay. NK cells are a population of large granular lymphocytes which have been associated with the surveillance of viral infection and tumor growth and metastases (Poste & Fidler, 1980; Herberman & Ortaldo, 1981) through their ability to lyse infected or neoplastic cells in a non-MHC-restricted fashion. In rodents, the acute administration of morphine has 835