Immunological correlation between morphine tolerance and the effect of naloxone in rats of different age

Abstract

In 3-6-week-old morphine-sensitive rats, in which morphine injection produced an analgetic effect, the serum titer of antimorphine antibodies 24 h postinjection is less than half that observed in morphine-resistant animals. Administration of naloxone to morphine-sensitive rats induces hyperalgesia and considerably raises the serum titer of antimorphine antibodies. Chronic injections of the same dose of morphine, which cause its analgetic effect to disappear, increase the titer of antibodies in morphine-sensitive rats 2-fold. In morphineresistant rats naloxone produces an analgetic effect followed by its gradual decay and disappearance in the course of chronic administration. Subsequent administration of morphine induces analgesia, raises the titer of antimorphine antibodies, and lowers the titer of antiidiotypic antibodies. Key Words: morphine; tolerance; naloxone; antimorphine antibodies; antiidiotypesAlthough the immune system is known to play a role in the formation of morphine tolerance -the disappearance of the effect of the initial dose of the narcotic, which develops especially rapidly in children [13] -this role remains poorly understood [12]. It has been found that antimorphine antibodies (AMAB) are produced in animals and man in response to morphine injection [4]. However, there are morphine-resistant individuals [1,14], in whom the reactions of the immune system have remained virtually unstudied. Recently, special interest has been paid to the detection of not only idiotypic but also antiidiotypic antibodies [2], in particular AMAB (AIAMAB). However, so far there is no clear evidence that these antibodies play a part in the mechanisms of morphine tolerance.Moreover, administration of naloxone to morphine-resistant animals has been previously found to induce an analgetic rather than hyperalgetic (as in The aim of the present study was to investigate the dynamics of formation of AMAB and AIAMAB in 3-6-week-old rats with morphine resistance and in the course of tolerance development and naloxone treatment. MATERIALS AND METHODSThe experiments were carried out on 3-6-week-old male albino Wistar rats weighing 50-75 g. Changes in nociception were evaluated on an Ugo Basile automatic analgesimeter by the latency of the tail flick (LTF) in response to 10 presentations of a thermal nociceptive stimulus every 1.5-2 min (tail-flick test). The device switches off automatically after 40 sec to avoid skin burn.Morphine hydrochloride (2 mg/kg) and naloxone (0.3 mg/kg, Sigma) were injected subcutaneously and intraperitoneally, respectively.