Abstract
Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment. Methods: Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression. Results: constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 μg/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the Kcnip3 gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats. Conclusion: Dysregulated circadian light exposure significantly compromises the efficacy of morphine’s antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.
Highlights
Opioids are important and effective analgesics for the management of peri/postoperative pain and cancer pain
We aim to explore the pain-behavior influence of constant light exposure and chronic melatonin infusion on neuropathic pain management with morphine infusion
constriction injury (CCI) rats living in the LL room manifested similar allodynia to CCI rats in the light/dark cycle (LD) room
Summary
Opioids are important and effective analgesics for the management of peri/postoperative pain and cancer pain. In the early 2000s, prescribed opioids for chronic pain increased in the United States (from approximately 100 to approximately 700 morphine milligram equivalents per person per year) and was accompanied by increasing unintended overdoses and associated deaths [4,5]. In response to this opioid epidemic, interventions including patient risk assessment, psychotherapy, the patient-centered taper of opioid dosage, and medication-assisted treatment have been proposed for the identification of patients at risk and to prevent those patients from falling into overdose and addiction [6]. Morris et al first reported a maximum antinociceptive effect of intraperitoneally injected (i.p.) morphine under dark conditions (21:00 h) in a mouse model [11]
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