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.
Highlights
Neuropathic pain is one of the most common complications of diabetes, occurring in nearly 50% of patients [1] and remains an important clinical problem due to resistance to classical opioid analgesic drugs, such as morphine [2,3,4,5,6]
While the mechanical and thermal allodynia as well as hyperalgesia induced by the administration of STZ were attenuated in animals treated with cobalt protoporphyrin IX (CoPP) at 5 or 10 mg/kg during 1 day (p
We demonstrated that the intraperitoneal administration of CoPP attenuated painful diabetic neuropathy and increased the antinociceptive effects of morphine
Summary
Neuropathic pain is one of the most common complications of diabetes, occurring in nearly 50% of patients [1] and remains an important clinical problem due to resistance to classical opioid analgesic drugs, such as morphine [2,3,4,5,6]. This loss in antinociceptive efficacy was described in diabetic animals following the systemic [2, 7], spinal [5, 8] and supraspinal [8] administration of μ-opioid receptor (MOR) agonists. The search of new strategies to treat painful diabetic neuropathy and/or improve the analgesic effects of morphine during diabetic neuropathy is required
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
