Implication of delta opioid receptor subtype 2 but not delta opioid receptor subtype 1 in the development of morphine analgesic tolerance in a rat model of chronic inflammatory pain.

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 MOPs and delta opioid receptors (DOPs) 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 DOPs 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 induced morphine analgesic tolerance in rats coping with chronic inflammatory pain. We then observed that blockade of DOPs with subcutaneous naltrindole (NTI), a selective DOP antagonist, significantly attenuated 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 naive animals. Previous pharmacological characterizations revealed the existence of DOP subtype 1 and DOP subtype 2. As opposed to NTI, 7-benzylidenenaltrexone and naltriben were reported to be selective DOP subtype 1 and DOP subtype 2 antagonists, respectively. Interestingly, naltriben but not 7-benzylidenenaltrexone was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that targeting of DOP subtype 2 with antagonists provides a valuable strategy to attenuate the analgesic tolerance that develops after repeated morphine administration in the setting of chronic inflammatory pain.