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Intense or sustained activation of peripheral nociceptors can induce central sensitization. This enhanced responsiveness to nociceptive input of the central nervous system primarily manifests as an increased sensitivity to painful mechanical pinprick stimuli extending beyond the site of injury (secondary mechanical hyperalgesia) and is thought to be a key mechanism in the development of chronic pain, such as persistent post-operative pain. It is increasingly recognized that emotional and cognitive factors can strongly influence the pain experience. Furthermore, through their potential effects on pain modulation circuits including descending pathways to the spinal cord, it has been hypothesized that these emotional and cognitive factors could constitute risk factors for the susceptibility to develop chronic pain. Here, we tested whether, in healthy volunteers, the experimental induction of central sensitization by peripheral nociceptive input can be modulated by selective spatial attention. While participants performed a somatosensory detection task that required focusing attention towards one of the forearms, secondary hyperalgesia was induced at both forearms using bilateral and simultaneous high-frequency electrical stimulation (HFS) of the skin. HFS induced an increased sensitivity to mechanical pinprick stimuli at both forearms, directly (T1) and 20 min (T2) after HFS, confirming the successful induction of secondary hyperalgesia at both forearms. Most importantly, at T2, the HFS-induced increase in pinprick sensitivity as well as the area of secondary hyperalgesia was greater at the attended arm as compared to the non-attended arm. This indicates that top-down attentional factors can modulate the development of central sensitization by peripheral nociceptive input, and that the focus of spatial attention, besides its modulatory effects on perception, can affect activity-dependent neuroplasticity.
Learn More >Understanding how the nervous system bridges sensation and behavior requires the elucidation of complex neural and molecular networks. Forward genetic approaches, such as screens conducted in C. elegans, have successfully identified genes required to process natural sensory stimuli. However, functional redundancy within the underlying neural circuits, which are often organized with multiple parallel neural pathways, limits our ability to identify 'neural pathway-specific genes', i.e. genes that are essential for the function of some, but not all of these redundant neural pathways. To overcome this limitation, we developed a 'forward optogenetics' screening strategy in which natural stimuli are initially replaced by the selective optogenetic activation of a specific neural pathway. We used this strategy to address the function of the polymodal FLP nociceptors mediating avoidance of noxious thermal and mechanical stimuli. According to our expectations, we identified both mutations in 'general' avoidance genes that broadly impact avoidance responses to a variety of natural noxious stimuli (unc-4, unc-83, and eat-4) and mutations that produce a narrower impact, more restricted to the FLP pathway (syd-2, unc-14 and unc-68). Through a detailed follow-up analysis, we further showed that the Ryanodine receptor UNC-68 acts cell-autonomously in FLP to adjust heat-evoked calcium signals and aversive behaviors. As a whole, our work (i) reveals the importance of properly regulated ER calcium release for FLP function, (ii) provides new entry points for new nociception research and (iii) demonstrates the utility of our forward optogenetic strategy, which can easily be transposed to analyze other neural pathways.
Learn More >Chronic pain is pain greater than 3 months duration that may result from disease, trauma, surgery, or unknown origin. The overlap between the psychological, behavioural, and management aspects of pain suggest that limbic brain neurochemistry plays a role in chronic pain pathology. Proton magnetic resonance spectroscopy (H-MRS) can evaluate in vivo brain metabolites including creatine, N-acetylaspartate, myo-inositol, choline, glutamate, glutamine, and gamma-aminobutyric acid in chronic pain; however, a comprehensive systemic review of metabolite expression patterns across all brain areas has yet to be performed.
Learn More >Burn injuries and associated complications present a major public health challenge. Many burn patients develop clinically intractable complications, including pain and other sensory disorders. Recent evidence has shown that dendritic spine neuropathology in spinal cord sensory and motor neurons accompanies central nervous system (CNS) or peripheral nervous system (PNS) trauma and disease. However, no research has investigated similar dendritic spine neuropathologies following a cutaneous thermal burn injury. In this retrospective investigation, we analyzed dendritic spine morphology and localization in alpha-motor neurons innervating a burn-injured area of the body (hind paw). To identify a molecular regulator of these dendritic spine changes, we further profiled motor neuron dendritic spines in adult mice treated with romidepsin, a clinically approved Pak1-inhibitor, or vehicle control at two postburn time points: Day 6 immediately after treatment, or Day 10 following drug withdrawal. In control treated mice, we observed an overall increase in dendritic spine density, including structurally mature spines with mushroom-shaped morphology. Pak1-inhibitor treatment reduced injury-induced changes to similar levels observed in animals without burn injury. The effectiveness of the Pak1-inhibitor was durable, since normalized dendritic spine profiles remained as long as 4 days despite drug withdrawal. This study is the first report of evidence demonstrating that a second-degree burn injury significantly affects motor neuron structure within the spinal cord. Furthermore, our results support the opportunity to study dendritic spine dysgenesis as a novel avenue to clarify the complexities of neurological disease following traumatic injury.
Learn More >Alcohol use disorder (AUD) and chronic pain are enduring and devastating conditions that share an intersecting epidemiology and neurobiology. Chronic alcohol use itself can produce a characteristic painful neuropathy, while the regular analgesic use of alcohol in the context of nociceptive sensitization and heightened affective pain sensitivity may promote negative reinforcement mechanisms that underlie AUD maintenance and progression. The goal of this review is to provide a broad translational framework that communicates research findings spanning preclinical and clinical studies, including a review of genetic, molecular, behavioral, and social mechanisms that facilitate interactions between persistent pain and alcohol use. We also consider recent evidence that will shape future investigations into novel treatment mechanisms for pain in individuals suffering from AUD.
Learn More >Many individuals with chronic pain report abnormal sensitivity to visual light, referred to as "photosensitivity" or "photophobia," yet how processing of light and nociceptive information come together remains a puzzle. Pain-modulating neurons in the rostral ventromedial medulla (RVM) have been shown to respond to bright visual light in male rats: activity of pain-enhancing ON-cells is increased, while that of pain-inhibiting OFF-cells is decreased. Since the RVM is the output node of a well-known pain modulation pathway, light-related input to these neurons could contribute to photosensitivity. The purpose of the present study was to fully characterize RVM ON- and OFF-cell responses to visual light by defining stimulus-response curves in male and female rats across a range of intensities (30 to 16,000 lx). We also determined if light-evoked responses are altered in animals subjected to persistent inflammation. We found that ON- and OFF-cells responded to relatively dim light (<1000 lx in naïve animals), with no difference between the sexes in threshold for light-evoked changes in firing or the percentage of responsive cells. Second, light-evoked suppression of OFF-cell firing was enhanced in persistent inflammation, with no change in light-evoked activation of ON-cells. These data indicate that pain-modulating neurons can be engaged by dim light, even under normal conditions. Further, they suggest that decreased descending inhibition during light exposure could contribute to reduced nociceptive thresholds in chronic pain states, resulting in light-induced somatic discomfort and aversion to light. Lastly, our findings argue for differences in how light and somatic stimuli engage RVM, and suggest that light-related input acts as a "top-down" regulatory input to RVM.
Learn More >Botulinum toxin A has the potential to be used for analgesia because of its anti-inflammatory effect. The utility of intra-articular injections of botulinum toxin A for knee osteoarthritis remains unclear. The aim of this study was to analyze the utility of such injections in knees with osteoarthritis.
Learn More >Kinematic data obtained during a movement task by individuals with chronic low back pain seem to be related to pain-related fear. General kinesiophobia assessments, such as Tampa Scale for Kinesiophobia, are often used to assess pain-related fear. However, these questionnaires could suffer from a lack of sensitivity and do not measure the fear of specific movements.
Learn More >Mary-Ann Fitzcharles et al. propose to introduce "regional fibromyalgia" as a new diagnosis. This commentary summarizes why this term is misleading but nonetheless the article may pave the way towards useful concepts for myofascial pains.
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