title: Pharmacological activation of heme oxygenase (HO)-1/carbon monoxide pathway prevents the development of peripheral neuropathic pain in Wistar rats.
abstract: Recent studies have emphasized the contribution of neuroinflammation and oxido-nitrosative stress to neuropathic pain. Both, heme oxygenase (HO)-1 and carbon monoxide (CO) play an important role in regulating free radical generation and inflammation. Herein, we investigated the role of HO-1/CO pathway, by using hemin, a selective HO activator, and CO-releasing molecule (CORM)-2, a CO-releasing agent, in rat sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain. CCI rats exhibited full development of behavioral hypersensitivity symptoms, including cold allodynia, mechanical and thermal hyperalgesia and also exhibit of a significant increase in spinal cord pro-inflammatory cytokines (TNF-α and IL-1β) and oxido-nitrosative stress markers, both in spinal cord and ipsilateral sciatic nerve homogenate. Spinal (10 and 30 μg/rat, intrathecal (i.t.)), but not systemic (5 and 10 mg/kg, subcutaneous (s.c.)), administration of hemin for 14 days significantly prevented the development of behavioral hypersensitivity. Further, simultaneous administration of hemin via spinal (10 μg/rat, i.t.) and systemic (5 mg/kg, s.c.) routes led to a more pronounced inhibition of the development of behavioral hypersensitivity. Further, administration of CORM-2 (1 and 5 mg/kg, s.c.), dose-dependently and most effectively, prevented the development of behavioral hypersensitivity. Both hemin and CORM-2 produced ameliorative beneficial effects that paralleled with the extent of reduction of oxido-nitrosative stress and pro-inflammatory cytokines. Also, hemin and CORM-2 significantly improved the levels of HO-1 and activity of anti-oxidant enzymes such as superoxide dismutase and catalase. Thus, it may be concluded that chronic pharmacological activation of HO-1/CO pathway may prevent the development of behavioral symptoms of neuropathic pain, through an activation of anti-inflammatory and anti-oxidant mechanisms.
authors.affiliation: Department of Pharmacology, I.S. F. College of Pharmacy, Moga, 142001, Punjab, India. krishnareddyvb@rediffmail.com
authors.forename: Krishna Reddy V
authors.initials: KR
authors.lastname: Bijjem
authors.forename: Satyanarayana S V
authors.initials: SS
authors.lastname: Padi
authors.forename: Pyare
authors.initials: P
authors.lastname: lal Sharma
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006427:Hemin / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000975:Antioxidants; D053583:Interleukin-1beta; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; D006427:Hemin; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1