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The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture, but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT1D receptors and not other 5-HT receptors. Selective 5-HT1D receptor antagonists blocked this agonist induced inhibition, though antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, since normal and injured rats were equally sensitive to 5-HT after blocking SERT, or to agonists not transported by SERT (zolmitriptan). Immunolabelling revealed that the 5-HT1D receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP positive C fibres, and eliminated by dorsal rhizotomy. 5-HT1D receptor labelling was not found on large proprioceptive afferents or alpha-motoneurons of the MSR. Thus, serotonergic inhibition of the MSR must act indirectly by modulating C fibre activity, opening up new possibilities for modulating reflex function and clonus via pain related pathways.
Learn More >We hypothesized that patients with characteristics of centralized pain (fibromyalgia (FM)-like phenotype) would be less likely to respond to radiofrequency ablation (RFA), which may explain some of the failures of this peripherally directed therapy.
Learn More >In this article, I review the concept of personalized pain management and consider how brain imaging and quantitative sensory testing can be used to derive biomarkers of chronic pain treatment outcome. I review how different modalities of brain imaging can be used to acquire information about brain structure and function and how this information can be linked to individual measures of 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.
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.
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