Moxonidine, a selective imidazoline-α₂-adrenergic receptor agonist, produces spinal synergistic antihyperalgesia with morphine in nerve-injured mice

Background: Moxonidine, a novel imidazoline-α₂-adrenergic receptor-selective analgesic, was recently identified as antinociceptive but has yet to be evaluated in neuropathic pain models. α₂-adrenergic receptor-selective analgesics, and high-efficacy opioids, effectively inhibit neuropathic pain behaviors in rodents. In contrast, morphine potency and efficacy decreases in states of neuropathic pain, both in rodents and in humans, but may be restored or enhanced by coadministration of morphine with α₂-adrenergic receptor-selective analgesics. The current experiments extend the evaluation of opioid-coadjuvant interactions in neuropathic subjects by testing the respective antihyperalgesic interactions of moxonidine and clonidine with morphine in a test of mechanical hyperalgesia. Methods: Nerve-injured mice (Chung model) were spinally administered moxonidine, clonidine, morphine, and the combinations moxonidine-morphine and clonidine-morphine. Hyperalgesia was detected by von Frey monofilament stimulation (3.3 mN) to the hind paws (plantar surface). The ED₅₀ values were calculated and the interactions tested by isobolographic analysis. Results: In nerve-injured mice, moxonidine, clonidine, and morphine all dose-dependently inhibited mechanical hyperalgesia. Furthermore, the combinations of moxonidine-morphine and clonidine-morphine resulted in substantial leftward shifts in the dose-response curves compared with those of each agonist administered separately. The calculated ED₅₀ values of the dose-response curves of these combinations were significantly lower than their corresponding theoretical additive ED₅₀ values. These results confirmed that both interactions were synergistic. Conclusions: Moxonidine and clonidine both synergize with morphine to inhibit paw withdrawal from nociceptive mechanical stimuli in nerve-injured mice.