Implication of DOP2 but not DOP1 in development of morphine analgesic tolerance in a rat model of chronic inflammatory pain

摘要

Opioids are well known for their robust analgesic effects. Chronic activation of mu opioid receptors (MOPs) is however accompanied by various unwanted effects such as analgesic tolerance. Among other mechanisms, interactions between MOP and delta opioid receptor (DOP) are thought to play an important role in morphine-induced behavioral adaptations. Interestingly, certain conditions such as inflammation enhance the function of the DOP through a MOP-dependent mechanism. Here, we investigated the role of DOP during the development of morphine-tolerance in an animal model of chronic inflammatory pain. Using behavioral approaches we first established that repeated systemic morphine treatment induces morphine analgesic tolerance in rats coping with chronic inflammatory pain. We then observed that blockade of DOP with subcutaneous naltrindole (NTI), a selective DOP antagonist, significantly attenuates the development of morphine tolerance in a dose-dependent manner. We confirmed that this effect was DOP-mediated by showing that an acute injection of NTI had no effect on morphine-induced analgesia in naïve animals. Previous pharmacological characterizations revealed the existence of DOP1 and DOP2 subtypes. As opposed to NTI, 7-benzylidenenaltrexone (BNTX) and naltriben (NTB) were reported to be selective DOP1 and DOP2 antagonists, respectively. Interestingly, NTB but not BNTX was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that targeting of DOP2 with antagonists provides a valuable strategy to attenuate the analgesic tolerance that develops after repeated morphine administration in the setting of chronic inflammatory pain.