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Migraine is a common, severe disease, affecting the brain and blood vessels, causing much pain, time missed from work and family, and severe disability. It affects approximately 12% of most Western populations studied and affects women three times more than men. Cluster headache is a much less common dysfunction of the hypothalamus, involving the sphenopalatine ganglion and other areas; it causes more frequent, shorter, and even more intense pain than migraine. The pain usually comes in cycles and is associated with ipsilateral autonomic features and associated with irritability and inability to stay still. It affects less than 0.1% of the population and is slightly more prevalent in men than women. Although we have some acute care and preventive medications for both types of headache, no treatment is optimal for each patient and some will not respond well or have significant adverse events to existing therapies.
Learn More >Reports in the literature have conflicting findings about an association between dry eye disease (DED) and migraine headaches.
Learn More >While evidence indicates that sigma-1 receptors (Sig-1Rs) play an important role in the induction of peripheral neuropathic pain, there is limited understanding of the role that the neurosteroidogenic enzymes, which produce Sig-1R endogenous ligands, play during the development of neuropathic pain. We examined whether sciatic nerve injury upregulates the neurosteroidogenic enzymes, cytochrome P450c17 and 3β-hydroxysteroid dehydrogenase (3β-HSD), which modulate the expression and/or activation of Sig-1Rs leading to the development of peripheral neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of P450c17, but not 3β-HSD, in the ipsilateral lumbar spinal cord dorsal horn at postoperative day 3. Intrathecal administration of the P450c17 inhibitor, ketoconazole during the induction phase of neuropathic pain (day 0 to day 3 post-surgery) significantly reduced the development of mechanical allodynia and thermal hyperalgesia in the ipsilateral hind paw. However, administration of the 3β-HSD inhibitor, trilostane had no effect on the development of neuropathic pain. Sciatic nerve injury increased astrocyte Sig-1R expression as well as dissociation of Sig-1Rs from BiP in the spinal cord. These increases were suppressed by administration of ketoconazole, but not by administration of trilostane. Co-administration of the Sig-1R agonist, PRE084 restored the development of mechanical allodynia originally suppressed by the ketoconazole administration. However, ketoconazole-induced inhibition of thermal hyperalgesia was not affected by co-administration of PRE084. Collectively these results demonstrate that early activation of P450c17 modulates the expression and activation of astrocyte Sig-1Rs, ultimately contributing to the development of mechanical allodynia induced by peripheral nerve injury.
Learn More >To study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH).
Learn More >Placebo analgesia is explained by two learning processes: classical conditioning and observational learning. A third learning process, operant conditioning, has not previously been investigated as a mechanism of placebo effects. We aimed to induce placebo analgesia by operant conditioning.
Learn More >Fibromyalgia (FM) is a generalized chronic pain condition associated with multiple cognitive impairments, including altered inhibitory processes. Inhibition is a key component of human executive functions and shares neural substrate with pain processing, which may explain the inhibitory deficits in FM. Here, we investigated the integrity of brain inhibitory mechanisms in these patients.
Learn More >Mechanical allodynia is pain caused by normally innocuous mechanical stimuli and is a cardinal and intractable symptom of neuropathic pain. Roles of low-threshold mechanoreceptors (LTMRs), including Aβ fibers, in mechanical allodynia have previously been proposed, but the necessity and sufficiency of LTMRs in allodynia have not been fully determined. Recent technological advances have made it possible to achieve subpopulation-specific ablation, silencing or stimulation, and to dissect and elucidate complex neuronal circuitry. Recent studies using an optogenetic approach have shown that activation of LTMRs, including Aβ fibers that genetically express channelrhodopsin-2, by illuminating blue light to the skin elicit morphine-resistant withdrawal behaviors after nerve damage. Whole-cell recording has revealed that optical Aβ stimulation after nerve injury causes excitation of lamina I dorsal horn neurons, which are normally silent by this stimulation. Moreover, Aβ stimulation after nerve injury results in activation of central amygdaloid neurons and produces aversive behaviors. In summary, these findings indicate that optogenetics is a powerful approach for investigating LTMR-derived pain (resembling mechanical allodynia) with sensory and emotional features after nerve injury and for discovering novel and effective drugs to treat neuropathic pain.
Learn More >Pain is a major comorbidity of sickle cell disease (SCD). Opioids are the mainstay for pain treatment but remain suboptimal. We discuss mechanism-based treatable targets devoid of opioids to prevent and/or treat SCD pain.
Learn More >Within- and between-study heterogeneity impede identification of valid primary headache biomarkers. Homogenous subgroup identification and investigation of differential biochemical profiles and networks within and across headache categories, based on statistical techniques, might promote biomarker discovery. When studying common primary headaches with a multifactorial etiology, variability might be captured at different levels (eg, genetics, clinical features, comorbidities, triggers). Moreover, focus on biochemical profiles instead of single compounds is crucial to develop strategies for accurate differential diagnosis.
Learn More >The opioid crisis constitutes a public health challenge at the intersection of two interrelated medical problems – opioid addiction and chronic pain. Overlap of the reward and pain circuits in the brain underlies the frequent comorbidity of chronic pain and opioid addiction, whereas inadequate support, treatment and health-care reimbursement for both of these conditions are major contributors underlying the magnitude of the problem. Neurologists are uniquely positioned to help address the opioid crisis, not only through their involvement in the management of chronic pain conditions but also because they can screen for and manage opioid use disorders. The new NIH Helping to End Addiction Long-term (HEAL) Initiative will support research into pain and opioid use disorders to help address the opioid crisis. Neurologists' involvement in basic, translational and clinical research is needed for the development of new pain therapeutics and biomarkers and interventions to prevent chronic pain and to prevent and treat opioid addiction.
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