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Cocaine- and Amphetamine-Regulated Transcript encodes an eponymous peptide, CARTp, which exerts diverse pharmacologic actions in the central and peripheral nervous systems, as well as in several endocrine organs, including pancreas. Here we review those diverse actions, the physiological relevance of which had remained unestablished until recently. With the identification of a CARTp receptor, GPR160, the physiologic importance and therapeutic potential of CARTp or analogs are being revealed. Not only is the CARTp-GPR160 interaction essential for the circadian regulation of appetite and thirst, but also for the transmission of nerve injury-induced pain. Molecular approaches now are uncovering additional, physiologically relevant actions and the development of acute, tissue-specific gene compromise approaches may reveal even more, physiologically relevant actions of this pluripotent ligand/receptor pair.
Learn More >Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LH) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LH neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LH neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LH projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LH activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LH neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.
Learn More >The Pain Catastrophizing Scale (PCS), a widely used tool to assess catastrophizing related to spinal disorders, shows valid psychometric properties in general but the minimal important change (MIC) is still not determined.
Learn More >Complex regional pain syndrome (CRPS) is a rare and severe chronic pain condition, with effective treatment options not established for many patients. The underlying pathophysiology remains unclear, but there is a growing appreciation for the role of central mechanisms which have formed the basis for brain-based therapies such as transcranial magnetic stimulation and mirror visual feedback (MVF). MVF has been deployed in the treatment of CRPS using both conventional mirrors and virtual reality (VR).
Learn More >: Erenumab, a monoclonal antibody targeting the receptor of calcitonin gene related peptide (CGRP), is the first disease-specific and mechanism-based treatment approved for the prevention of migraine. Although the safety and tolerability data from randomized trials are clear, the physiological effects of CGRP rise reasonable concerns. We aimed to evaluate the current evidence for safety and tolerability related to erenumab use in migraine.: This review outlines the severe adverse events (AEs), common AEs, AEs leading to treatment discontinuation and AEs of special interest, reported in all phase 2, phase 3, open label and observational studies with erenumab in migraine. Individual safety reports were also included in the systematic review of evidence.: No safety and tolerability flags were detected in this review. The most common AE are local skin reactions and constipation. No severe AEs, or frequent AEs leading to treatment discontinuation were detected. Treatment is well tolerated. The only AE of interest that may play a role in decision making and treatment monitoring is constipation. These findings are in line with previous safety reports, further highlighting the substantial tolerability and safety profile of the modern anti-CGRP monoclonal antibodies for the prevention of migraine.
Learn More >Chronic pain is associated with mental and physical health difficulties and is prevalent among veterans. Cannabis has been put forth as a treatment for chronic pain, and changes in laws, attitudes, and use patterns have occurred over the last two decades. Differences in prevalence of non-medical cannabis use and cannabis use disorder (CUD) were examined across two groups: veterans/non-veterans and those reporting/not reporting recent pain. Data from the National Epidemiologic Survey on Alcohol and Related Conditions-III (2012-2013; n=36,309) were analyzed using logistic regression. Prevalence Differences (PD) for three cannabis outcomes: (1) past-year non-medical cannabis use, (2) frequent (≥3 times a week) non-medical use, and (3) DSM-5 CUD were estimated for those reporting recent moderate-severe pain (veterans/non-veterans), and veterans reporting/not reporting recent pain. Difference in differences were calculated to investigate prevalence differences on outcomes associated with residence in a state with medical cannabis laws (MCLs). Associations between physical and mental health and cannabis variables were tested. Results indicated that the prevalence of recent pain was greater among veterans (PD=7.25%, 95% CI [4.90, 9.60]). Among veterans, the prevalence of frequent cannabis use was greater among those with pain (PD=1.92%, 98% CI [0.21, 3.63]), and, among veterans residing in a state with MCLs, the prevalence of CUD was greater among those reporting recent pain (PD=3.88%, 98% CI [0.36, 7.39]). Findings failed to support the hypothesis that cannabis use improves mental or physical health for veterans with pain. Providers treating veterans with pain in MCL states should monitor such patients closely for CUD.
Learn More >Disrupted cognition and chronic musculoskeletal pain (CMP) are prevalent experiences among Gulf War Veterans (GWV). A negative association between CMP and cognition (i.e., chronic pain-related cognitive interference) has been observed in some chronic pain populations but has not been evaluated in GWV. Additional research suggests that disrupted cognition in GWV with CMP may be exacerbated by stressing the nociceptive system. Therefore, we compared cognitive performance and related neural activity between CMP and healthy control (CO) GWV in the absence and presence of experimental pain.
Learn More >The literature on conditioned pain modulation (CPM) is inconclusive in relation to low-back pain and it is unclear how CPM affects temporal summation as a proxy of central pain integration. The aim of this study was to examine whether the CPM effect would be different on pain induced by temporal summation than single stimuli in a group of low back pain patients.
Learn More >Pain is among the most widespread chronic health condition confronting society today and our inability to manage chronic pain contributes to the opioid abuse epidemic in America. The immune system is known to contribute to acute and chronic pain, but only limited therapeutic treatments such as non-steroid anti-inflammatory drugs have resulted from this knowledge. The last decade has shed light on neuro-immune interactions mediating the development, maintenance, and resolution of chronic pain. Here, we do not aim to perform a comprehensive review of all immune mechanisms involved in chronic pain, but to briefly review the contribution of the main cytokines and immune cells (macrophages, microglia, mast cells and T cells) to chronic pain. Given the urgent need to address the Pain crisis, we provocatively propose to repurpose/reposition FDA-approved immunomodulatory drugs for their potential to alleviate chronic pain. Repositioning or repurposing offers an attractive way to accelerate the arrival of new analgesics.
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