Effects of the imidazoline I-2 receptor agonist 2-BFI on the development of tolerance to and behavioural/physical dependence on morphine in rats
Background and PurposeThis study examined the effects of imidazoline I-2 receptor agonists on the development of tolerance to and physical dependence on repeated morphine treatment in rats.
Experimental ApproachTwo groups of rats (n=9 per group) were trained to lever press for sucrose (10%) presentation under a fixed-ratio 10 schedule. The rate-suppressing effects of the opioid receptor ligands morphine and naltrexone and the I-2 receptor agonist 2-BFI were examined weekly in rats treated with either daily morphine (20mgkg(-1), s.c.), alone or in combination with 2-BFI (10mgkg(-1)) for 3weeks. Changes in body weight were measured following naltrexone tests in both groups of rats. In separate experiments, the antinociceptive effects of morphine were assessed using a warm-water tail-withdrawal procedure in rats before and after daily treatments (7days) with morphine (32mgkg(-1), i.p.) alone or in combination with various doses of the I-2 receptor agonists 2-BFI, BU224 and CR4056.
Key ResultsDaily treatment for 3 weeks, with morphine in combination with 2-BFI produced significantly less tolerance to the rate-suppressing effects of morphine and produced a decreased sensitivity to the rate-suppressing effects of naltrexone as well as decreased naltrexone-induced weight loss, compared with morphine-alone group. Repeated treatment for 7days with morphine produced antinociceptive tolerance, which was attenuated by co-administration with 2-BFI, BU224 or CR4056.
Conclusions and ImplicationsImidazoline I-2 receptor agonists attenuated the development of tolerance to and physical dependence on morphine, further supporting the therapeutic potential of combining I-2 receptor agonists and opioids for pain treatment.