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.

Exogenous induction of HO-1 alleviates vincristine-induced neuropathic pain by reducing spinal glial activation in mice

“…Peripheral HO-1 also mediates the analgesic effect of epibatidine in the formalin test (Egea et al, 2009). However, intrathecal, but not systemic injection of hemin suppressed the development of CCI-induced neuropathic pain (Bijjem et al, 2013). Moreover, simultaneous injection of hemin via spinal and systemic routes led to a more profound inhibition of the development of behavioral hypersensitivity (Bijjem et al, 2013).…”

“…The peripheral upregulation of HO-1 reduces the inflammatory pain induced by peripheral injection of formalin (Nascimento and Branco, 2007), interleukin-1β (IL-1β) (Steiner et al, 2001), or complete Freund's adjuvant (CFA) (Kaur et al, 2011). Pharmacological activation of HO-1 also prevented sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain, and reduced expression of pro-inflammatory cytokines in the spinal cord (Bijjem et al, 2013). However, the mechanisms underlying the antinociceptive effect of HO-1 have not been studied in depth.…”

H2Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain

“…Carbon monoxide-releasing molecule 2 (CORM-2) (Sigma-Aldrich, St. Louis, MO), HO-1 inhibitor Sn (IV) protoporphyrin IX dihydrochloride (SnPP-IX) (Frontier Scientific, Lancashire, UK), and hemin (Sanjay Biological, Amritsar, India) were obtained and given as reported in previous studies [3]. The catheter was purchased from Becton Dickinson (Sparks, MD, USA).…”

“…Neuropathic pain is the most common category of chronic pain. It may be triggered or initiated in the peripheral or central nervous system by a primary lesion or dysfunction and is characterized by persistent pain, tactile allodynia, or hyperalgesia [2,3]. Because of its elusive cellular and physiopathologic mechanisms, neuropathic pain is difficult to cure, and the strongest painkillers may not be able to completely relieve the patient's pain.…”

Gasotransmitters in Vascular Complications of Diabetes

“…The activation of HO/CO signaling reduced symptoms of neuropathic pain, presumably by the activation of anti-inflammatory and antioxidant mechanisms (68). CO exerts antinociceptive effects and increases the antiallodynic and antihyperalgesic efficacy of morphine in chronic inflammation and neuropathic pain (69)-the latter strictly dependant on NO produced by nNOS and iNOS.…”