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.
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Acknowledgments
We express our sincere thanks to the management, ISF College of Pharmacy, Moga, Punjab, India for providing necessary facilities. The authors are also thankful to AICTE New Delhi, India (RPS grant: File.No. 8023/BOR/RID/RPS-193/2008-09) and School of Biomedical Sciences, The University of Edinburgh, Edinburgh (CAEN fund), for providing financial support.
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Bijjem, K.R.V., Padi, S.S.V. & lal Sharma, P. Pharmacological activation of heme oxygenase (HO)-1/carbon monoxide pathway prevents the development of peripheral neuropathic pain in Wistar rats. Naunyn-Schmiedeberg's Arch Pharmacol 386, 79–90 (2013). https://doi.org/10.1007/s00210-012-0816-1
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DOI: https://doi.org/10.1007/s00210-012-0816-1