Antinociceptive activity of α4β2 neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain

• Published in: European journal of pharmacology Vol. 668; no. 1-2; pp. 155 - 162
• Main Authors: Nirogi, Ramakrishna, Jayarajan, Pradeep, Abraham, Renny, Shanmuganathan, Dhanalakshmi, Rasheed, Mohammed Abdul, Royapalley, Praveen Kumar, Goura, Venkatesh
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.10.2011; Elsevier
• Subjects: A-366833; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Azabicyclo Compounds - pharmacology; Azabicyclo Compounds - therapeutic use; Biological and medical sciences; Complete Freund's adjuvant; Constriction; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Diabetes Complications - drug therapy; Diabetes neuropathy; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Freund's Adjuvant - adverse effects; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Inflammation - chemically induced; Inflammation - drug therapy; Inflammation - etiology; Ligation; Male; Medical sciences; Nerve ligation model; Nervous system (semeiology, syndromes); Neuralgia - chemically induced; Neuralgia - drug therapy; Neuralgia - etiology; Neurology; Nicotinic acetylcholine receptor agonist; Nicotinic Agonists - pharmacology; Nicotinic Agonists - therapeutic use; Pharmacology. Drug treatments; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - metabolism; Rotarod Performance Test; Sciatic Nerve - surgery; Vincristine; Complete Freund's adjuvant; Vincristine; Nerve ligation model; Nicotinic acetylcholine receptor agonist; Diabetes neuropathy; A-366833; Endocrinopathy; Antineoplastic agent; Nervous system diseases; Agonist; Diabetes mellitus; Inflammation; Neuropathy; chemical ligation; Neuropathic pain; Alkaloid; Cholinergic receptor; Analgesic; Models; Neuralgia; Neurological disorder; Antimitotic; Nicotinic receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.06.032

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 6mg/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.