Selective potentiation of gabapentin-mediated antinociception in the rat formalin test by the nicotinic acetylcholine receptor agonist ABT-594

The treatment of chronic pain is hampered by various issues including multiple underlying mechanisms contributing to disease pathology and treatment-related toxicity concerns. These can be partially circumvented by combining mechanistically distinct drugs with the aim of selectively potentiating analgesia as opposed to side-effects. This approach has been used to assess the antinociceptive efficacy of the nicotinic acetylcholine (nACh) receptor agonist ABT-594 when combined with the antiepileptic drug gabapentin, the mu-opioid receptor agonist morphine or the antidepressant drug duloxetine in the rat formalin test. Alone, ABT-594 (0.01-0.3 mg/kg) dose-dependently attenuated spontaneous flinching behaviour during first (P1) and second (P2) phase. Similarly, P1, interphase and P2 flinching were variously attenuated by gabapentin (25-200 mg/kg), morphine (0.3-3 mg/kg) and duloxetine (3-60 mg/kg). Remarkably, a completely inactive dose of ABT-594 reduced the dose of gabapentin required to produce antinociception during P1 by 4-8 fold and during P2 by 8-16 fold. This striking potentiation was blocked by mecamylamine and indicative of analgesic synergy. Similar, albeit less consistent results (3-10 fold potency increase) were obtained with morphine/ABT-594. Although a 3 fold increase in P2 antinociceptive potency was obtained with duloxetine in the presence of ABT-594, a corresponding increase in efficacy was lacking. Indeed, a mechanistically relevant reduction in antinociceptive efficacy and potency of duloxetine/ABT-594 occurred during interphase. Thus, activation of the nicotinic cholinergic system differentially modulates the antinociceptive actions of distinct mechanism of action compounds, and provides a novel framework for nACh receptor modulators mediating analgesia in the putative absence of adverse events associated with this mechanism of action.