The Induction of Heme Oxygenase 1 Decreases Painful Diabetic Neuropathy and Enhances the Antinociceptive Effects of Morphine in Diabetic Mice

Abstract

Painful diabetic neuropathy is a common complication of diabetes mellitus which is poorly controlled by conventional analgesics. This study investigates if treatment with an heme oxygenase 1 (HO-1) inducer, cobalt protoporphyrin IX (CoPP), could modulate the allodynia and hyperalgesia induced by diabetes and enhanced the antinociceptive effects of morphine. In a diabetic mice model induced by the injection of streptozotocin (STZ), we evaluated the antiallodynic and antihyperalgesic effects produced by the intraperitoneal administration of 5 and 10 mg/kg of CoPP at several days after its administration. The antinociceptive actions produced by the systemic administration of morphine alone or combined with CoPP were also evaluated. In addition, the effects of CoPP treatment on the expression of HO-1, the microglial activation marker (CD11b/c), the inducible nitric oxide synthase (NOS2) and μ-opioid receptors (MOR), were also assessed. Our results showed that the administration of 10 mg/kg of CoPP during 5 consecutive days completely blocked the mechanical and thermal hypersensitivity induced by diabetes. These effects are accompanied by the increased spinal cord, dorsal root ganglia and sciatic nerve protein levels of HO-1. In addition, the STZ-induced activation of microglia and overexpression of NOS2 in the spinal cord were inhibited by CoPP treatment. Furthermore, the antinociceptive effects of morphine were enhanced by CoPP treatment and reversed by the administration of an HO-1 inhibitor, tin protoporphyrin IX (SnPP). The spinal cord expression of MOR was also increased by CoPP treatment in diabetic mice. In conclusion, our data provide the first evidence that the induction of HO-1 attenuated STZ-induced painful diabetic neuropathy and enhanced the antinociceptive effects of morphine via inhibition of microglia activation and NOS2 overexpression as well as by increasing the spinal cord levels of MOR. This study proposes the administration of CoPP alone or combined with morphine as an interesting therapeutic approach for the treatment of painful diabetic neuropathy.

The induction of the transcription factor Nrf2 enhances the antinociceptive effects of delta-opioid receptors in diabetic mice

“…Moreover, protein levels of the antioxidant enzyme HO-1 were significantly increased in the sciatic nerve from db/db mice treated with SFN. In agreement with our data, an increased expression of HO-1 in several tissues from type 1 diabetic animals treated with different Nrf2 or HO-1 inducers compounds has been also previously reported [14, 28, 36, 37]. Tacking account the corroborated antinociceptive properties produced by the activation of HO-1 under inflammatory and neuropathic pain conditions [8, 11, 14], our results suggested that the improvement of the mechanical allodynia induced by SFN in db/db treated mice might be also mediated by enhancing the HO-1 expression in the sciatic nerve of these animals.…”

Wrapping With Basic Fibroblast Growth Factor‐Impregnated Collagen Sheet Reduces Rat Sciatic Nerve Allodynia

“…Consistent with previous studies on the effects of vein wrapping, we found that bFGF/CS stimulates Hmox1 mRNA and HO‐1 protein expression, while PBS/CS does not. Previous studies have shown that HO‐1 induction results in anti‐nociceptive effects and alleviation of neuropathic pain . Our results suggest that bFGF/CS‐mediated HO‐1 expression may contribute to pain relief.…”

Vein wrapping facilitates basic fibroblast growth factor‐induced heme oxygenase‐1 expression following chronic nerve constriction injury

“…Several in vitro and in vivo studies have demonstrated that anti‐oxidants relieve neuropathic pain resulting from peripheral nerve injury . For example, heme oxygenase‐1 (HO‐1) is a rate‐limiting enzyme that catalyzes the oxidative degeneration of heme into biliverdin, carbon monoxide, and iron.…”

“…For example, heme oxygenase‐1 (HO‐1) is a rate‐limiting enzyme that catalyzes the oxidative degeneration of heme into biliverdin, carbon monoxide, and iron. HO‐1 over‐expression or induction is associated with potent anti‐inflammatory and antinociceptive effects, both in vitro and in mice, and also alleviates neuropathic pain induced by sciatic nerve injury . A recent study reported that bFGF induces HO‐1 expression in spinal cord astrocytes in vitro .…”