Antinociception synergy between the peripheral and spinal sites of the heme oxygenase-carbon monoxide pathway

Abstract

We have shown that the peripheral and spinal cord heme oxygenase (HO)-carbon monoxide (CO)-soluble guanylate cyclasecGMP pathways play an important role in antinociception in the rat experimental formalin model. Our objective was to determine if there is synergism between peripheral (paw) and spinal HO-CO pathways in nociception. Rats were handled and adapted to the experimental environment for a few days before the formalin test, in which 50 μL of a 1% formalin was injected subcutaneously into the dorsal surface of the right hind paw. The animals were then observed for 1 h and the frequency of flinching behavior was taken to represent the nociceptive response. Thirty minutes before the test, rats were pretreated with intrathecal injections of the HO inhibitor, zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) or heme-lysinate, which is a substrate of the HO pathway. The paw treatments took place 20 min before the test. Low doses of ZnDPBG did not increase nociception, while a low heme-lysinate dose did not change flinching behavior after paw or spinal injections. Combined subactive spinal (50 nmol) and peripheral (40 nmol) low doses of ZnDPBG induced hypernociception (increase of 80% in the first and 25% in the second phase flinching), whereas combined spinal-peripheral heme-lysinate (50 and 30 nmol) led to second phase antinociception (40% reduction in flinching). These findings suggest a synergy between the peripheral and spinal HO-CO pathways. Local activation of the HO system probably regulates the nociception initiation in peripheral tissue and participates in buffering the emerging nociceptive signals at the peripheral and spinal sites of action. In short, an antinociceptive synergy exists between peripheral and spinal HO pathways, which may reduce the doses required and side effects.

Carbon monoxide: A gas that modulates nociception

“…For example, there is a significant increase in nociceptive response of rats in a formalin test when intrathecally treated with zinc deuteroporphyrin 2,4‐bis glycol (ZnDPBG, an HO inhibitor; Nascimento and Branco,2008). The results indicate that HO induction has an antinociceptive action in spinal cord, which is further confirmed in a more recent study by the same group (Nascimento and Branco,2009). This inconsistency could be due to different procedures when performing the intrathecal injection (Nascimento and Branco,2008).…”

“…Another study also showed that HO‐1 induction by epibatidine has antinociceptive effect in the formalin test (Egea et al,2009). These data indicate that the effects of CO on nociception in CNS and PNS might be distinct, although there is evidence showing that CO has an antinociceptive action in spinal cord (Nascimento and Branco,2008,2009).…”

“…However, there have been few studies on the role of CO in PNS in inflammatory or neuropathic pain. Local administration of HO inhibitor and the gas CO in inflamed paws of rats increases and reduces nociceptive behavioral response in inflammatory pain models, respectively (Steiner et al,2001; Nascimento and Branco,2007,2009). This indicates that endogenous CO produced by HO plays an antinociceptive role at peripheral sites in inflammatory pain.…”

Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: Etiological contribution to complex regional pain syndromes (Part I)

“…Chronic pharmacological activation of heme oxygenase (HO)-1/CO pathway may prevent the development of behavioral symptoms of neuropathic pain, through an activation of anti-inflammatory and anti-oxidant mechanisms [62]. In further, HO-CO-cGMP pathway plays a key phasic antinociceptive role modulating noninflammatory acute pain and inflammatory pain, and an antinociceptive synergy exists between peripheral and spinal HO-CO pathways [63]. Application of both carbon monoxide-releasing molecule II (CORM-2) and heme oxygenase 1 inducer (cobalt protoporphyrin IX, CoPP) improved the local antinociceptive effects of morphine during chronic inflammatory and neuropathic pain by interaction with NO [64] and enhancing MOR peripheral expression and inhibiting spinal microglial activation and overexpression of NOS suggesting that an interaction between CO and NO systems is taking place following nerve injury.…”

The Effect of Scraping Therapy on Perimenopausal Syndrome: A Synthesis of Evidence

“…In transgenic mouse models, the occurrence of therapeutic petechiae following scraping therapy implicated the destruction of erythrocytes which in turn triggered molecular changes to stimulate the upregulation of stress-inducible heme oxygenase-1 (HO-1). As a well-known heat shock protein, HO-1 has anti-nociceptive, anti-inflammatory, and hepatoprotective effects [7,8]. …”