title: Selective potentiation of gabapentin-mediated antinociception in the rat formalin test by the nicotinic acetylcholine receptor agonist ABT-594.
abstract: 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.
authors.affiliation: Department of Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750, Ballerup, Denmark. gmu@neurosearch.dk
authors.forename: Gordon
authors.initials: G
authors.lastname: Munro
authors.forename: Helene
authors.initials: H
authors.lastname: Dyhr
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
mesh_terms: D000588:Amines / Q000627:therapeutic use*; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001384:Azetidines / Q000627:therapeutic use*; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000068736:Duloxetine Hydrochloride; D005106:Exploratory Behavior / Q000187:drug effects; D000077206:Gabapentin; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009020:Morphine / Q000627:therapeutic use; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D000588:Amines; D000700:Analgesics; D001384:Azetidines; D003509:Cyclohexanecarboxylic Acids; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D013876:Thiophenes; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D008464:Mecamylamine; D009020:Morphine; D000068736:Duloxetine Hydrochloride