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 α2δ1 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 α2δ1 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.

The Antinociceptive, Antioxidant and Anti-Inflammatory Effects of 5-Fluoro-2-Oxindole during Inflammatory Pain

“…SnPP was administered 30 min after 5-fluoro-2-oxindole injection and animals were tested 30 min after SnPP injection ( n = 6 animals per group). The dose of SnPP was selected in accordance with other studies [ 18 , 23 ].…”

The role of carbon monoxide, heme oxygenase 1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids

“…57,59 Other studies have further shown that CORM-2 increases the analgesic effects of buprenorphine 51 and that both CoPP and CORM-2 improve the antiallodynic actions of the gabapentinoids, pregabalin, and gabapentin, by increasing HO-1 and Ca 2+ channel α2δ1 subunit gene expression and inhibiting microglial activation and the overexpression of TNF-α in the spinal cords of animals with neuropathic pain. 18 The Nrf2 transcription factor modulates oxidative stress and the inflammatory and pronociceptive pathways in the peripheral and central nervous systems. 140,141 A crucial factor for the antioxidant activity of Nrf2 is the modulation of the transcription of numerous genes that encode antioxidant and detoxifying enzymes, such as HO-1, NQO1, superoxide dismutase 1, and glutathione peroxidase.…”

“…In the last years, several studies have evaluated the anti-inflammatory and antinociceptive effects of carbon monoxide as well as those produced by activators of inducible heme oxygenase 1 (HO-1) or the nuclear factor-2 erythroid factor-2 (Nrf2) transcription factor alone or in combination with other analgesic compounds in different preclinical pain models. [11][12][13][14][15][16][17][18][19][20][21][22] In this review, we examine, in chronological order, the results obtained by us and other research groups regarding the effects of HO-1 and carbon monoxide in pain, their mechanisms of action during chronic pain, and their effects on the antinociceptive actions of opioids, cannabinoids, and other analgesics during chronic pain. We also revised the effects of Nrf2 transcription factor activators in pain, their effects in the analgesic actions of opioids and cannabinoids as well as on the emotional disorders accompanying chronic pain.…”

“…46 These treatments also inhibit inflammatory and monoarthritis pain, 11,14,16,46,48,49 neuropathic pain caused by total or partial sciatic nerve ligation, and pain provoked by spinal nerve injury. 15,17,18,30,46,[50][51][52][53][54] These compounds have also been shown to inhibit neuropathic pain caused by vincristine administration 55,56 or associated with type 1 or type 2 diabetes [57][58][59][60] (Figure 1). Intraspinal injection of a recombinant lentivirus overexpressing HO-1 also suppresses neuropathic pain induced by spinal nerve ligation in mice.…”

Immune responses in beta-thalassaemia: heme oxygenase 1 reduces cytokine production and bactericidal activity of human leucocytes

“…Hemin (ferriprotoporphyrin IX), a derivative chemical from heme, was used as a representative of heme-induced HO-1 expression 35,36 . Application of cobalt protoporphyrin IX (CoPP) as HO-1 inducer and tin protoporphyrin IX (SnPP) as HO-1 inhibitor are widely used in previous researches 29,30,37,38 . Hemin and CoPP induced HO-1 mRNA expression as expected (Fig.…”