Effects of the imidazoline I2 receptor agonist 2-BFI on the development of tolerance to and behavioural/physical dependence on morphine in rats.

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This study examined the effects of imidazoline I2 receptor agonists on the development of tolerance to and physical dependence on repeated morphine treatment in rats. Two 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 I2 receptor agonist 2-BFI were examined weekly in rats treated with either daily morphine (20mg·kg(-1) , s.c.), alone or in combination with 2-BFI (10mg·kg(-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 (32mg·kg(-1) , i.p.) alone or in combination with various doses of the I2 receptor agonists 2-BFI, BU224 and CR4056. Daily 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. Imidazoline I2 receptor agonists attenuated the development of tolerance to and physical dependence on morphine, further supporting the therapeutic potential of combining I2 receptor agonists and opioids for pain treatment.