Dissociation of immunosuppressive and nociceptive effects of fentanyl, but not morphine, after repeated administration in mice: Fentanyl-induced sensitization to LPS

Immunosuppressive morphine actions are well characterized, but other opiates are less studied. The objectives of this work were: (a) to compare the acute effects of morphine and fentanyl to inhibit early peritoneal LPS-induced TNFα release; (b) to find if, as in the case of morphine, intraperitoneal mast cells (MCs) are the target of fentanyl's immunosuppressive actions; and (c) to analyze if repeated opiate administration induces tolerance to opiate immunosuppressive effects. Independent groups of mice received a single i.p. injection of morphine (0.1-10 mg/kg) or fentanyl (0.001-0.1 mg/kg) 10 min prior to LPS (1 mg/kg). Peritoneal TNFα levels were determined 1 h later. The effects of fentanyl were analyzed in MC-deficient mice (W-sh) and in W-sh mice reconstituted with bone marrow-derived MCs. Other animals received 6 or 10 doses of morphine (10 mg/kg, 3×/day) or fentanyl (0.1 mg/kg 3×/day) and were then challenged with LPS. Fentanyl was equally effective and 1000× more potent than morphine to inhibit i.p. LPS-induced TNFα release and this was dependent on intraperitoneal MCs. Repeated morphine administration induced tolerance to both antinociception and inhibition of response to endotoxin. Repeated fentanyl injection did not induce significant antinociceptive tolerance, but, interestingly, produced sensitization to LPS. In conclusion: (1) opiates with different analgesic potency also differ in their potency to induce immunosuppression; (2) MCs are the cellular target of the immunosuppressive actions of fentanyl here studied; (3) in contrast with morphine, tolerance to fentanyl's immunosuppressive actions can be dissociated from tolerance to its antinociceptive effects.