Pain
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Cutaneous allodynia is an established marker for central sensitization in migraine. There is debate whether cutaneous allodynia may also occur in cluster headache, another episodic headache disorder. Here, we examined the presence and severity of allodynia in a large well-defined nationwide population of people with cluster headache. ⋯ Female gender (odds ratio [OR] 2.05, 95% confidence interval [95% CI] 1.28-3.29), low age at onset (OR 0.98, 95% CI 0.96-0.99), lifetime depression (OR 1.63, 95% CI 1.06-2.50), comorbid migraine (OR 1.96, 95% CI 1.02-3.79), and having recent attacks (OR 1.80, 95% CI 1.13-2.86), but not duration of attacks and chronic cluster headache, were independent risk factors for allodynia. The high prevalence of cutaneous allodynia with similar risk factors for allodynia as found for migraine suggests that central sensitization, like in migraine, also occurs in cluster headache. In clinical practice, awareness that people with cluster headache may suffer from allodynia can in the future be an important feature in treatment options.
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Opioids are the gold standard for pharmacological treatment of neuropathic pain, but their analgesic effects are unsatisfactory in part due to nerve injury-induced downregulation of opioid receptors in dorsal root ganglia (DRG) neurons. How nerve injury drives such downregulation remains elusive. DNA methyltransferase (DNMT)-triggered DNA methylation represses gene expression. ⋯ Mechanistically, DNMT3a regulation of Oprm1 gene expression required the methyl-CpG-binding protein 1, MBD1, as MBD1 knockout resulted in the decreased binding of DNMT3a to the Oprm1 gene promoter and blocked the DNMT3a-triggered repression of Oprm1 gene expression in DRG neurons. These data suggest that DNMT3a is required for nerve injury-induced and MBD1-mediated epigenetic silencing of the MOR and KOR in the injured DRG. DNMT3a inhibition may serve as a promising adjuvant therapy for opioid use in neuropathic pain management.