title: Antinociceptive activity of α4β2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain.
abstract: Nerve injury, diabetes and cancer therapies are often associated with painful neuropathy. The mechanism underlying neuropathic pain remains poorly understood. The current therapies have limited efficacy and are associated with dose-limiting side effects. Compounds which act at nicotinic acetylcholine receptors have also been reported to show antinociceptive activity. Among those, tebanicline (ABT-594) a potent nicotinic acetylcholine receptor agonist demonstrated analgesic effects across a broad range of preclinical models of nociceptive and neuropathic pain. Another nicotinic acetylcholine receptor agonist, 5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) from the same group produced significant antinociceptive effects in writhing pain (abdominal constriction), acute thermal pain (hot box), persistent chemical pain (formalin induced) and neuropathic pain. In the present study, we have demonstrated the efficacy of A-366833 in rat models of chronic constriction injury, partial sciatic nerve ligation, spinal nerve ligation, diabetes, chemotherapy induced neuropathic pain and complete Freund's adjuvant induced inflammatory pain. A-366833 (1, 3 and 6 mg/kg) produced significant antihyperalgesic effects in partial sciatic nerve ligation, chronic constriction injury and spinal nerve ligation models. In the diabetic and chemotherapy induced neuropathic models compound exerted antinociceptive activity and reduction in the mechanical hyperalgesia was observed. A-366833 dose dependently attenuated mechanical hyperalgesia in complete Freund's adjuvant induced inflammatory pain model. These results demonstrated broad-spectrum antinociceptive properties of A-366833 in both neuropathic and inflammatory pain models.
authors.affiliation: Department of Pharmacology, Discovery Research, Suven Life Sciences Ltd, Serene Chambers, Road No 5, Avenue-7, Banjara Hills, Hyderabad, 500034, India. nvsrk@suven.com
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Nirogi
authors.forename: Sugin Lal
authors.initials: SL
authors.lastname: Jabaris
authors.forename: Pradeep
authors.initials: P
authors.lastname: Jayarajan
authors.forename: Renny
authors.initials: R
authors.lastname: Abraham
authors.forename: Dhanalakshmi
authors.initials: D
authors.lastname: Shanmuganathan
authors.forename: Mohammed Abdul
authors.initials: MA
authors.lastname: Rasheed
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Royapalley
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Goura
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D003250:Constriction; D048909:Diabetes Complications / Q000188:drug therapy; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions; D005620:Freund's Adjuvant / Q000009:adverse effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology; D008026:Ligation; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D045442:Rotarod Performance Test; D012584:Sciatic Nerve / Q000601:surgery
chemical_list: C568846:5-(3,6-diazabicyclo(3.2.0)heptan-6-yl)nicotinonitrile; D000700:Analgesics; D053961:Azabicyclo Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D005620:Freund's Adjuvant