Moxonidine, a selective imadazoline-alpha(2)-adrenergic receptor agonist, produces spinal synergistic antihyperalgesia with morphine in nerve-injuredmice

Background Moxonidine, a novel imidazoline-alpha(2)-adrenergic receptor-sel ective analgesic, was recently identified as antinociceptive but has yet to be evaluated in neuropathic pain models. alpha(2)-adrenergic receptor-sele ctive analgesics, and high-efficacy opioids, effectively inhibit neuropathi c pain behaviors in rodents. In contrast, morphine potency and efficacy dec reases in states of neuropathic pain, both In rodents and in humans, but ma y be restored or enhanced by coadministration of morphine with alpha(2)-adr energic receptor-selective analgesics. The current experiments extend the e valuation of opioid-coadjuvant interactions in neuropathic subjects by test ing the respective antihyperalgesic interactions of moxonidine and clonidin e with morphine in a test of mechanical hyperalgesia. Methods: Nerve-injured mice (Chung model) were spinally administered moxoni dine, clonidine, morphine, and the combinations moxonidine-morphine and clo nidine-morphine, Hyperalgesia was detected by von Frey monofilament stimula tion (3.3 mN) to the hind paws (plantar surface). The ED50 values were calc ulated and the interactions tested by isobolographic analysis. Results: In nerve-injured mice, moxonidine, clonidine, and morphine all dos e-dependently inhibited mechanical hyperalgesia. Furthermore, the combinati ons of moxonidine-morphine and clonidine-morphine resulted in substantial l eftward shifts in the dose-response curves compared with those of each agon ist administered separately. The calculated ED50 values of the dose-respons e curves of these combinations were significantly lower than their correspo nding theoretical additive ED50 values. These results confirmed that both i nteractions were synergistic. Conclusions: Moxonidine and clonidine both synergize with morphine to inhib it paw withdrawal from nociceptive mechanical stimuli in nerve-injured mice .