Chronic pain and its associated comorbidities are difficult to treat, even when the most potent analgesic compounds are used. Thus, research on new strategies to effectively relieve nociceptive and/or emotional disorders accompanying chronic pain is essential. Several studies have demonstrated the anti-inflammatory and antinociceptive effects of different carbon monoxide-releasing molecules (CO-RMs), inducible heme oxygenase 1 (HO-1), and nuclear factor-2 erythroid factor-2 (Nrf2) transcription factor activators in several models of acute and chronic pain caused by inflammation, nerve injury or diabetes. More recently, the antidepressant and/or anxiolytic effects of several Nrf2 transcription factor inducers were demonstrated in a model of chronic neuropathic pain. These effects are mainly produced by inhibition of oxidative stress, inflammation, glial activation, mitogen-activated protein kinases and/or phosphoinositide 3-kinase/phospho-protein kinase B phosphorylation in the peripheral and/or central nervous system. Other studies also demonstrated that the analgesic effects of opioids and cannabinoids are improved when these drugs are coadministered with CO-RMs, HO-1 or Nrf2 activators in different preclinical pain models and that these improvements are generally mediated by upregulation or prevention of the downregulation of µ-opioid receptors, δ-opioid receptors and/or cannabinoid 2 receptors in the setting of chronic pain. We reviewed all these studies as well as studies on the mechanisms of action underlying the effects of CO-RMs, HO-1, and Nrf2 activators in chronic pain. In summary, activation of the Nrf2/HO-1/carbon monoxide signaling pathway alone and/or in combination with the administration of specific analgesics is a valid strategy for the treatment of chronic pain and some associated emotional disorders.
Keywords: Nrf2 transcription factor; cannabinoids; carbon monoxide; heme oxygenase 1; opioids; pain.
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