ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model.
ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.
Lynch
James J
JJ
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Department R4N5, Bldg. AP9A-LL, 100 Abbott Park Road, Abbott Park, IL 60064-6115, USA. james.j.lynch@abbott.com
Wade
Carrie L
CL
Mikusa
Joseph P
JP
Decker
Michael W
MW
Honore
Prisca
P
D000109:Acetylcholine / Q000819:agonists / Q000494:pharmacology; D000698:Analgesia / Q000379:methods*; D000818:Animals; D001384:Azetidines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002714:Chlorisondamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D006801:Humans; D008464:Mecamylamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D009270:Naloxone / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D001384:Azetidines; D018722:Nicotinic Agonists; D011725:Pyridines; D009270:Naloxone; D014750:Vincristine; D008464:Mecamylamine; D002714:Chlorisondamine; D000109:Acetylcholine