Browse by Audience
Cation channels of the transient receptor potential (TRP) family serve important physiological roles by opening in response to diverse intra- and extracellular stimuli that regulate their lower or upper gates. Despite extensive studies, the mechanism coupling these gates has remained obscure. Previous structures have failed to resolve extracellular loops, known in the TRPV subfamily as 'pore turrets', which are proximal to the upper gates. We established the importance of the pore turret through activity assays and by solving structures of rat TRPV2, both with and without an intact turret at resolutions of 4.0 Å and 3.6 Å, respectively. These structures resolve the full-length pore turret and reveal fully open and partially open states of TRPV2, both with unoccupied vanilloid pockets. Our results suggest a mechanism by which physiological signals, such as lipid binding, can regulate the lower gate and couple to the upper gate through a pore-turret-facilitated mechanism.
Learn More >By definition, post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI) is not associated with brain structural abnormalities that are seen on routine clinical inspection of brain images. However, subtle brain structural abnormalities, as well as functional abnormalities, detected via research imaging techniques yield insights into the pathophysiology of PTH. The objective of this manuscript is to summarize published findings regarding research imaging of the brain in PTH attributed to mTBI. For this narrative review, PubMed was searched using the terms "post-traumatic headache" or "post-concussion headache" and "imaging" or "magnetic resonance imaging" or "research imaging" or "positron emission tomography". Articles were chosen for inclusion based on their relevance to the topic. Ten articles were ultimately included within this review. The studies investigated white matter tract integrity and functional connectivity in acute PTH, structural measures, white matter tract integrity, cerebral blood flow, and functional connectivity in persistent PTH (PPTH), and proton spectroscopy in both acute and persistent PTH. The articles demonstrate that acute and persistent PTH are associated with abnormalities in brain structure, that acute and persistent PTH are also associated with abnormalities in brain function, that it might be possible to predict the persistence of PTH using brain imaging findings, and that there are differences in imaging findings when comparing PTH to healthy controls and when comparing PTH to migraine. Although it is not entirely clear if the imaging findings are directly attributable to PTH as opposed to the underlying TBI or other post-TBI symptoms, correlations between the imaging findings with headache frequency and headache resolution suggest a true relationship between the imaging findings and PTH. PTH attributed to mTBI is associated with abnormalities in brain structure and function that can be detected via research imaging. Additional studies are needed to determine the specificity of the findings for PTH, to differentiate findings attributed to PTH from those attributed to the underlying TBI and coexistent post-TBI symptoms, and to determine the accuracy of imaging findings for predicting the development of PPTH.
Learn More >The comorbidity of chronic pain and opioid addiction is a serious problem that has been growing with the practice of prescribing opioids for chronic pain. Neuroimaging research has shown that chronic pain and opioid dependence both affect brain structure and function, but this is the first study to evaluate the neurophysiological alterations in patients with comorbid chronic pain and addiction. Eighteen participants with chronic low back pain and opioid addiction were compared with eighteen age- and sex-matched healthy individuals in a pain-induction fMRI task. Unified structural equation modeling (SEM) with Lagrange multiplier (LM) testing yielded a network model of pain processing for patient and control groups based on 19 defined regions. Tests of differences between groups on specific regression parameters were determined on a path-by-path basis using -tests corrected for the number of comparisons. Patients with the chronic pain and addiction comorbidity had increased connection strengths; many of these connections were interhemispheric and spanned regions involved in sensory, affective, and cognitive processes. The affected regions included those that are commonly altered in chronic pain or addiction alone, indicating that this comorbidity manifests with neurological symptoms of both disorders. Understanding the neural mechanisms involved in the comorbidity is crucial to finding a comprehensive treatment, rather than treating the symptoms individually.
Learn More >Although electroacupuncture (EA) has become a worldwide practice, little is understood about its precise target in the central nervous system (CNS) and the cell type-specific analgesia mechanism. In the present study, we found that EA has significant antinociceptive effects both in inflammatory and neuropathic pain models. Chemogenetic inhibition of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG) replicated the effects of EA, whereas the combination of chemogenetic activation of GABAergic neurons and chemogenetic inhibition of glutamatergic neurons in the vlPAG was needed to reverse the effects of EA. Specifically knocking out CB1 receptors on GABAergic neurons in the vlPAG abolished the EA effect on pain hypersensitivity, while specifically knocking out CB1 receptors on glutamatergic neurons attenuated only a small portion of the EA effect. EA synchronously inhibits GABAergic neurons and activates glutamatergic neurons in the vlPAG through CB1 receptors to produce EA-induced analgesia. The CB1 receptors on GABAergic neurons localized in the vlPAG was the basis of the EA effect on pain hypersensitivity. This study provides new experimental evidence that EA can bidirectionally regulate GABAergic neurons and glutamatergic neurons via the CB1 receptors of the vlPAG to produce analgesia effects.
Learn More >This study aimed to investigate the effect of oral treatment with ketotifen, a mast cell (MC) stabilizer, in a rat model of surgically induced endometriosis. At 14 days after Sprague-Dawley rats had surgery, they were treated with ketotifen (1 or 10 mg/kg/day). Pain behaviors were evaluated 3 days prior to surgery and then at 7, 14, 21, and 28 days after surgery. At day 28, rats were sacrificed and all samples were then processed for biochemical studies. We found that ketotifen-treated rats showed significantly shorter duration of hyperalgesia (<0.05); smaller cyst diameter (<0.05) and lower histopathologic score (<0.001); significantly lower MC number and degranulation (<0.001), blood vessel number (<0.001), lower expression levels of nerve growth factor (<0.001), cyclooxygenase-2 (<0.001), intercellular cell adhesion molecule-1 (<0.001), and vascular endothelial growth factor (<0.05) in cysts, and nerve growth factor (<0.001) and transient receptor potential cation channel, subfamily V, member 1 (<0.001) in dorsal root ganglia; and lower histamine (<0.05) and tumor necrosis factor-alpha (<0.05) concentrations in serum compared with placebo-treated animal subjects. Oral treatment with ketotifen significantly suppressed the development of hyperalgesia, probably by modulating MC activity in cysts, thereby reducing peripheral sensitization due to noxious signals from endometriotic lesions. Our results suggest that ketotifen may inhibit the development of endometriotic lesions and hyperalgesia in rats.
Learn More >Complex Regional Pain Syndrome (CRPS) is characterized by pain, motor and inflammatory symptoms usually affecting one limb. Cognitive difficulties have been reported to affect patients' ability to represent, perceive and use their affected limb. It is debated whether these difficulties result from deficits in controlling goal-directed movements in space or from a learned strategy to protect the affected limb. In order to dissociate the two hypotheses, patients with upper-limb CRPS were asked to move with their unaffected hand towards visual targets projected at different positions on a horizontal semi-reflexive mirror. By means of a robotic handle placed below the screen, they were asked to move a cursor, to reach and cross lines at their estimated midpoint. In some of the stimulation series, the affected hand was placed below the mirror so that some lines appeared projected onto that hand. Vision of the hands and the robotic handle was preserved or prevented by opening or closing a shutter below the mirror. Lines were displayed on the mirror according to which part of the body was affected (ispi- vs. contralateral) and the actual position of the affected hand (inside vs. outside the workspace). Comparatively to control participants, CRPS patients generally biased their estimation by bisecting the lines towards their left side, irrelative of which part of the body was affected and the position of the affected hand, both in ipsi- and contralateral space, with only a few exceptions. Our results are in line with previous studies having described a visuospatial deficit in CRPS patients and discard the explanation of observed symptoms in terms of learned nonuse strategies, as only the unaffected hand was used to perform the task. It is suggested that CRPS patients can display difficulties to perform tasks requesting visuo-motor coordination, reflecting the complex cortical reorganization occurring in CRPS.
Learn More >Fibromyalgia (FM) is a generalized chronic pain syndrome of unknown aetiology. Although FM patients frequently complain of cognitive dysfunction, this is one of the least studied symptoms. Research on brain activity associated with the perceived cognitive impairment is particularly scarce. To address this gap, we recorded the brain electrical activity in participants during a cognitive control task.
Learn More >Although analyses of pooled clinical trial data have reported how international populations respond to pregabalin by baseline neuropathic pain (NeP) severity, no studies have evaluated this specifically in patients from Japan. Thus, this post hoc pooled analysis evaluated the efficacy of pregabalin in Japanese subjects for treating moderate or severe baseline NeP.
Learn More >Chronic pain of uncertain etiology often presents a challenge to both patients and their health care providers. It is a complex condition influenced by structural and physiological changes in the peripheral and central nervous systems, and it directly influences, and is modulated by, psychological well-being and personality style, mood, sleep, activity level and social circumstances. Consequently, in order to effectively treat the pain, all of these need to be evaluated and addressed. An effective management strategy takes a multidisciplinary biopsychosocial approach, with review of all current medications and identification and careful withdrawal of those that may actually be contributing to ongoing pain. The management approach is primarily nonpharmacological, with carefully considered addition of medication, beginning with pain-modulating treatments, if necessary. In this article, we present a primary care approach to the assessment and management of a patient with chronic pain where the cause cannot be identified.
Learn More >The present study aimed to identify microRNAs (miRNAs) that are involved in neuropathic pain and predict their corresponding roles in the pathogenesis and development process of neuropathic pain. The rat model of neuropathic pain caused by spared nerve injury (SNI) was established in Sprague-Dawley male rats, followed by small RNA sequencing of the L3-L6 dorsal root ganglion. Real-time PCR was performed to validate the differently expressed miRNAs. Functional verification was performed by intrathecally injecting the animals with miRNA agomir. A total of 72 differentially expressed miRNAs were identified in the SNI rats, including 33 upregulated and 39 downregulated miRNAs. The results of qPCR further verified the expression levels of rno-miR-6215 (P=0.015), rno-miR-1224 (P=0.030), rno-miR-1249 (P=0.038), and rno-miR-488-3p (P=0.048), which were all significantly downregulated in the SNI rats compared to the control ones. The majority of differentially expressed miRNAs were associated with phosphorylation, intracellular signal transduction, and cell death. Target prediction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses suggested that these differentially expressed miRNAs targeted genes that are related to axon guidance, focal adhesion, and Ras and Wnt signaling pathways. Moreover, miR-1224 agomir significantly alleviated SNI-induced neuropathic pain. The current findings provide new insights into the role of miRNAs in the pathogenesis of neuropathic pain.
Learn More >