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Chronic pain in adults with sickle cell disease (SCD) may be the result of altered processing in the central nervous system as indicated by quantitative sensory testing (QST). Sensory pain quality descriptors on the McGill Pain Questionnaire (MPQ) are indicators of typical or altered pain mechanisms but have not been validated with QST-derived classifications.
Learn More >Chronic itch is a debilitating condition characterised by excessive scratching and is a symptom frequently reported in skin diseases such as atopic dermatitis. It has been proposed that release of the cysteine protease Cathepsin S (CatS) from skin keratinocytes or immune cells resident in or infiltrating the skin could act as a pruritogen in chronic itch conditions. CatS is known to activate protease-activated receptor 2 (PAR2). We therefore hypothesised that enzymatic activation of neuronally expressed PAR2 by CatS was responsible for activation of sensory neurons and transmission of itch signals. Intradermally-injected human recombinant (hr)-CatS or the PAR2 agonist, SLIGRL-NH behaved as pruritogens by causing scratching behaviour in mice. Hr-CatS-induced scratching behaviour was prevented by CatS inhibitors and PAR2 antagonists and reduced by 50% in TRPV1 mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1 mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca] following incubation with hr-CatS, and the percentage of neurons that responded to hr-CatS decreased in the presence of a PAR2 antagonist or in cultures of neurons from TRPV1 mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons.
Learn More >Chronic low back pain (CLBP) is a major cause of global disability and improving management is essential. Acceptance and Commitment Therapy (ACT) is a promising treatment for chronic pain but has not been modified for physical therapy. This randomized controlled trial (RCT) compared physical therapy informed by Acceptance and Commitment Therapy (PACT) against standard care physical therapy for patients with CLBP. Patients with CLBP (duration ≥12 weeks, mean 3 years) were recruited from physical therapy clinics in four UK public hospitals. The Roland-Morris Disability Questionnaire (RMDQ) at 3 months' post randomization was the primary outcome. 248 participants (59% female, mean age=48) were recruited and 219 (88•3%) completed measures at 3 and/or 12 months' follow-up. At 3 months, PACT participants reported better outcomes for disability (RMDQ mean difference =1•07, p=0•037, 95%CI -2•08 to -0•07, d=0•2), Patient Specific Functioning (p=0.008), SF12 physical health (p=0.032), and treatment credibility (p<0.001). At 12 months' follow-up there were no significant differences between groups. PACT was acceptable to patients and clinicians and feasible to deliver. Physical therapists incorporated psychological principles successfully and treatment was delivered with high (≥80%) fidelity. Our results may inform the management of CLBP, with potential benefits for patients, health care providers and society. PERSPECTIVE: Psychologically informed physical therapy has great potential but there are challenges in implementation. The training and support included in the PACT trial enabled the intervention to be delivered as planned. This successfully reduced disability in the short but not long term. Findings could inform physical therapists' treatment of CLBP.
Learn More >We aimed to assess the safety of opioids in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials.
Learn More >Radiotherapy-related pain is a common adverse reaction with a high incidence among cancer patients undergoing radiotherapy and remarkably reduces the quality of life. However, the mechanisms of ionizing radiation (IR)-induced pain are largely unknown. In present study, mice were treated with 20 Gy X-ray to establish IR-induced pain model. X-ray evoked a prolonged mechanical, heat and cold allodynia in mice. Transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) were significantly upregulated in lumbar dorsal root ganglion (DRG). The mechanical and heat allodynia could be transiently reverted by intrathecal injection of TRPV1 antagonist capsazepine and TRPA1 antagonist HC-030031. Additionally, the phosphorylated ERK and JNK in pain neural pathway were induced by X-ray treatment. Our findings indicated activation of TRPA1 and TRPV1 is essential for the development of X-ray-induced allodynia. Furthermore, our findings suggest targeting on TRPV1 and TRPA1 may be promising prevention strategies for X-ray-induced allodynia in clinical practice.
Learn More >In mice, spared nerve injury replicates symptoms of human neuropathic pain and induces upregulation of many genes in somatosensory neurons. Here we used single cell transcriptomics to probe the effects of partial infraorbital transection of the trigeminal nerve at the cellular level. Uninjured neurons were unaffected by transection of major nerve branches, segregating into many different classes. In marked contrast, axotomy rapidly transformed damaged neurons into just two new and closely-related classes where almost all original identity was lost. Remarkably, sensory neurons also adopted this transcriptomic state following various minor peripheral injuries. By genetically marking injured neurons, we showed that the injury-induced transformation was reversible, with damaged cells slowly reacquiring normal gene expression profiles. Thus, our data expose transcriptomic plasticity, previously thought of as a driver of chronic pain, as a programed response to many types of injury and a potential mechanism for regulating sensation during wound healing.
Learn More >The spinal dorsal horn is the first relay structure coding for pain transmission and modulation. Previous anatomical and electrophysiological studies have examined spinal dorsal horn circuitry, functional studies of circuit connections and network activity. Further work is required to understand spinal cord sensory information processing that underlies pathological neuropathic pain states. Our previous studies suggest that peripheral nerve injury enhances presynaptic excitatory input onto spinal superficial dorsal horn neurons, which in turn contributes to pathologic nociception. The potential changes in local postsynaptic circuits in the dorsal horn that lead to pathologically heightened behavioral responses to pain remain largely unexplored. We combined whole cell electrophysiological recordings with laser scanning photostimulation (LSPS) to test whether the spinal nerve ligation (SNL) mouse model of neuropathic pain leads to alterations in the functional connectivity of spinal cord circuits including lamina II excitatory interneurons. Here we show that SNL enhances excitation and decreases inhibition to lamina II excitatory interneurons along with their increased glutamate-evoked excitability. The enhanced excitatory postsynaptic input and connectivity evoked by SNL eventually return to normal levels concurrently with the resolution of the neuropathic pain states. The physiological pattern highly correlates with mouse pain behaviors following SNL, supporting a neurophysiological mechanism of central sensitization and neuropathic pain that is functionally localized to the spinal dorsal horn. Together, these data support that SNL induces functional changes in synaptic input and connectivity to lamina II excitatory interneurons that code for pain perception, and thus provide new insights into the mechanism and locus of pain hypersensitivity. Neuropathic pain presumably results from alterations in neuronal circuits that process nociception. This form of pain is often maladaptive. The contribution of circuit connections and detailed local spinal cord circuits underlying neuropathic pain are not well understood. Here, we apply laser-scanning photostimulation (LSPS) combined with whole cell recordings to investigate local circuit connectivity onto the lamina II interneurons during and after recovery following spinal nerve ligation that causes pathological neuropathic pain. The present study sheds light on local circuit organization in spinal dorsal horn and shows that reciprocal changes occur in local excitatory interneurons during both peak and after the gradual normalization of neuropathic pain. This elucidates nociceptive processing changes during and after neuropathic pain conditions and suggests new treatments.
Learn More >TRPM8 is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo-EM structures of TRPM8 in ligand-free, antagonist- or calcium-bound forms, revealing how robust conformational changes give rise to two non-conducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.
Learn More >The study reported here investigated the role of the central vascular endothelial growth factor-A (VEGF-A) pathway in the development of trigeminal neuropathic pain following nerve injury. A Sprague-Dawley rat model of trigeminal neuropathic pain was produced using malpositioned dental implants. The left mandibular second molar was extracted under anesthesia and replaced with a miniature dental implant to induce injury to the inferior alveolar nerve. The inferior alveolar nerve injury produced a significant upregulation of astrocytic VEGF-A expression in the medullary dorsal horn. The nerve injury-induced mechanical allodynia was inhibited by an intracisternal infusion of VEGF-A164 antibody. Although both VEGF-A Receptor 1 (VEGF-A R1; colocalized with the blood-brain barrier) and VEGF-A Receptor 2 (VEGF-A R2; colocalized with astrocytes) participated in the development of trigeminal neuropathic pain following nerve injury, only the intracisternal infusion of a VEGF-A R1 antibody, and not that of a VEGF-A R2 antibody, inhibited the increased blood-brain barrier (BBB) permeability produced by nerve injury. Finally, we confirmed the participation of the central VEGF-A pathway in the development of trigeminal neuropathic pain by reducing VEGF-A expression using VEGF-A164 siRNA. This suppression of VEGF-A produced significant prolonged anti-allodynic effects. These results suggest that the central VEGF-A pathway plays a key role in the development of trigeminal neuropathic pain following nerve injury through two separate pathways: VEGF-A R1 and VEGF-A R2. Hence, a blockade of the central VEGF-A pathway provides a new therapeutic avenue for the treatment of trigeminal neuropathic pain.
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