Study on the possible similar mechanism of ultra low dose-induced hyperalgesia and development of tolerance to analgesia in male rats: an study based on the role of Gs signaling pathway

Introduction: Ultra low dose (ULD) morphine induces hyperalgesia which is mediated by excitatory Gscoupled opioid receptors. This study was designed to investigate the development of tolerance to hyperalgesic effect of morphine. Also we attempt to seek possible similarity, in view of Gs proteins, between hyperalgesic effect of ULD and hyperalgesic effect after tolerance to HD. Method: Male Wistar rats weighing 180-220 g were used. All injections were given intra peritoneally. For tolerance induction animals received ULD or HD for 5 days and at the 6th day tail flick test was performed before and 30 min after morphine administration. Effect of pretreatment with ULD on analgesic tolerance was assessed by injection of ULD before HD in 5 consecutive days then TF record was done after HD injection on 6th day. Time interval between injections was 15 minutes. Cross tolerance assay was measured by recording the response to a specified dose in 6th day after 5 days treatment with another dose. Oseltamivir, as a GM1 ganglioside inhibitor, was used for inhibition of Gs signaling. . Results: Our results showed that: 1) tolerance was established after chronic injection of ultra low dose (ULD) of morphine. 2) Pre-treatment by ULD reduced tolerance to therapeutic dose of morphine. 3) Cross tolerance to analgesia was observed after chronic administration of ULD. 4) Combination therapy with oseltamivir blocked hyperalgesia; reduced analgesic tolerance and attenuated the development of tolerance to hyperalgesic effect of morphine. Conclusion: The results showed the partially common mechanism for development of tolerance to hyperalgesic and analgesic effect of morphine. Signaling through Gs proteins seems to be a common pathway.