Heme oxygenase-1 inducer and carbon monoxide-releasing molecule enhance the effects of gabapentinoids by modulating glial activation during neuropathic pain in mice.

ABSTRACT: Introduction:Neuropathic pain is one of the most difficult-to-treat symptoms. Although gabapentinoids are classified as first-line drugs, they have only modest efficacy. Objectives:The aim of this study was to investigate whether treatment with the heme oxygenase-1 (HO-1) inducer cobalt protoporphyrin IX (CoPP) or the carbon monoxide-releasing molecule tricarbonyldichlororuthenium (II) dimer (CORM-2) can enhance the antinociceptive effects produced by gabapentinoids in mice with neuropathic pain. Methods:Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. The mechanical threshold was tested using von Frey filaments. The expression of spinal HO-1, HO-2, the Ca2+ channel ?2?1 subunit, microglial markers, and M1 or M2 microglial markers was examined using reverse transcription polymerase chain reaction. Results:Treatment with CoPP or CORM-2 alleviated mechanical allodynia induced by SNI. CoPP or CORM-2 enhanced the antiallodynic effects of gabapentinoids (pregabalin or gabapentin) during SNI-induced mechanical allodynia. HO-1 inhibitor tin protoporphyrin IX (SnPP) prevented the antiallodynic effects of gabapentinoids (pregabalin or gabapentin) during SNI-induced mechanical allodynia. CoPP or CORM-2 increased HO-1 and Ca2+ channel ?2?1 subunit gene expression and the decreased gene expression of microglial markers, M1 microglial marker, or tumor necrosis factor in the ipsilateral spinal dorsal horn of mice with SNI. SnPP prevented HO-1 induction and glial inhibition, which were produced by gabapentinoids during SNI-induced mechanical allodynia. Conclusions:This study suggests that HO-1 plays crucial roles in the antiallodynic effects of gabapentinoids. Gabapentinoids attenuate the glial activation induced by SNI and some of these effects are mediated by HO-1.

SUBMITTER: Godai K 

PROVIDER: S-EPMC6181470 | biostudies-literature | 2018 Sep-Oct

REPOSITORIES: biostudies-literature