PAIN®最新文献

Abstract: Chronic pain is a serious and prevalent condition that can affect many facets of life. However, uncertainty remains regarding the strength of the association between chronic pain and death and whether the association is causal. We investigate the pain-mortality relationship using data from 19,971 participants aged 51+ years in the 1998 wave of the U.S. Health and Retirement Study. Propensity score matching and inverse probability weighting are combined with Cox proportional hazards models to investigate whether exposure to chronic pain (moderate or severe) has a causal effect on mortality over a 20-year follow-up period. Hazard ratios (HRs) with 95% confidence intervals (CIs) are reported. Before adjusting for confounding, we find a strong association between chronic pain and mortality (HR: 1.32, 95% CI: 1.26-1.38). After adjusting for confounding by sociodemographic and health variables using a range of propensity score methods, the estimated increase in mortality hazard caused by pain is more modest (5%-9%) and the results are often also compatible with no causal effect (95% CIs for HRs narrowly contain 1.0). This attenuation highlights the role of confounders of the pain-mortality relationship as potentially modifiable upstream risk factors for mortality. Posing the depressive symptoms variable as a mediator rather than a confounder of the pain-mortality relationship resulted in stronger evidence of a modest causal effect of pain on mortality (eg, HR: 1.08, 95% CI: 1.01-1.15). Future work is required to model exposure-confounder feedback loops and investigate the potentially cumulative causal effect of chronic pain at multiple time points on mortality.

Abstract: Osteoarthritis (OA) is a highly prevalent and disabling joint disease, characterized by pathological progressive joint deformation and clinical symptoms of pain. Disease-modifying treatments remain unavailable, and pain-mitigation is often suboptimal, but recent studies suggest beneficial effects by inhibition of the voltage-gated sodium channel Na V 1.7. We previously identified compound 194 as an indirect inhibitor of Na V 1.7 by preventing SUMOylation of the Na V 1.7-trafficking protein, collapsin response mediator protein 2. Compound 194 reduces the functional activity of Na V 1.7 channels and produces effective analgesia in a variety of acute and neuropathic pain models. However, its effectiveness has not yet been evaluated in models of OA. Here, we explore the effects of 194 on pain-related outcomes in the OA-like monoiodoacetate model using behavioral assessment, biochemistry, novel in vivo fiber photometry, and patch clamp electrophysiology. We found that the monoiodoacetate model induced (1) increased pain-like behaviors and calcium responses of glutamatergic neurons in the parabrachial nucleus after evoked cold and mechanical stimuli, (2) conditioned place aversion to mechanical stimulation, (3) functional weight bearing asymmetry, (4) increased sodium currents in dorsal root ganglia neurons, and (5) increased calcitonin gene-related peptide-release in the spinal cord. Crucially, administration of 194 improved all these pain-related outcomes. Collectively, these findings support indirect inhibition of Na V 1.7 as an effective treatment of OA-related pain through the inhibition of collapsin response mediator protein 2-SUMOylation via compound 194.

Abstract: Neuropathic pain is one of the most challenging types of pain to diagnose and treat, a problem exacerbated by the lack of a quantitative biomarker. Recently, several clinical and preclinical studies have shown that neuropathic pain induces cerebral hemodynamic changes as a result of neuroplasticity in the brain. Our hypothesis in this study is that neuropathic pain leads to cerebral hemodynamic changes over postoperative time in a spinal nerve ligation (SNL) rat model, which has not been longitudinally explored previously. Furthermore, by identifying multiple regional hemodynamic features that are the most distinct between SNL and sham groups, where the sham group underwent only an incision without SNL, it may be possible to classify the SNL group regardless of when the onset of pain occurs. We investigate cerebral hemodynamic changes using dynamic susceptibility contrast magnetic resonance imaging in a rat model up to 28 days after ligating L5/L6 spinal nerves. We trained a linear support vector machine with relative cerebral blood volume data from different brain regions and found that the prediction model trained on the nucleus accumbens, motor cortex, pretectal area, and thalamus classified the SNL group and sham group at a 79.27% balanced accuracy, regardless of when the onset of pain occurred (SNL/sham: 60/45 data points). From the use of the SNL model without prior knowledge of the onset time of pain, the current findings highlight the potential of relative cerebral blood volume in the 4 highlighted brain regions as a biomarker for neuropathic pain.

Abstract: The mesopontine tegmental anesthesia area (MPTA) is a focal brainstem locus which, when exposed to GABAergic agents, induces brain-state transitioning from wakefulness to unconsciousness. Correspondingly, MPTA lesions render animals relatively insensitive to GABAergic anesthetics delivered systemically. Using chemogenetics, we recently identified a neuronal subpopulation within the MPTA whose excitation induces this same pro-anesthetic effect. However, very few of these "effector-neurons" express synaptic γ2-containing GABAA receptor isoforms and none express extrasynaptic δ-subunit containing receptors, suggesting that they are not the direct cellular target of GABAergic agents. Here we used pharmacological tools in rats to define the molecular target(s) of GABAergics in the MPTA. GABA microinjected into the MPTA at nanomolar concentrations, selective for GABAAδ-Rs, proved to be pro-anesthetic as was blocking GABA reuptake. Likewise, low-concentration gaboxadol/THIP, also selective for GABAAδ-Rs, was effective, whereas benzodiazepines and zolpidem, which selectively target GABAAγ2-Rs, were not. The GABAergic anesthetics pentobarbital and propofol proved pro-anesthetic when applied to the MPTA at the low concentrations present in the brain after systemic dosing. Glycinergic agonists which are inhibitory, but infective on GABAAδ-Rs, and other non-GABAergic agonists tested, were at most only marginally effective. We conclude that GABAAδ-Rs are the primary molecular target of GABAergic anesthetics in the MPTA. Immunolabeling revealed that this GABAA-R isoform is expressed exclusively by a distinct subpopulation of MPTA "δ-cells" that reside in close apposition to effector neurons. This suggests that during wakefulness, δ-cells serve as inhibitory interneurons which, when silenced by GABAergic agents, disinhibit (excite) the effector-neurons, triggering transition to unconsciousness.

Abstract: The mechanism causing cold pain in humans is unresolved. Animal data suggest a nonredundant contribution to cold pain for transient receptor potential channels TRPM8 and TRPA1 for detection and voltage-gated sodium channels NaV1.7 and NaV1.8 for conduction at these temperatures. We established an intradermal injection-based cold pain model, which allows pharmacologically addressing molecular targets at the site of cooling. Lidocaine, added to the injection solution as positive control, largely reduced cold-induced pain in 36 volunteers. The 4 mentioned molecular targets were blocked by antagonists in a double-blinded crossover trial. Pain induced by 3°C intradermal fluid was not reduced to a relevant extent by any of the 4 antagonists alone or by the quadruple combination. However, the temperature threshold for cold pain appeared shifted by the inhibition of TRPA1, TRPM8, and NaV1.7 and to a lesser extent by NaV1.8 inhibition, 4-fold inhibition decreased the threshold by 5.8°C. Further mechanisms contributing to human cold pain need to be considered.

Abstract: Previous preclinical and translational studies suggest that tissue trauma related to bony fracture and intervertebral disk disruption initiates the formation of pronociceptive antibodies that support chronic musculoskeletal pain conditions. This study tested this hypothesis in the monosodium iodoacetate (MIA) mouse model of osteoarthritis (OA) and extended the findings using OA patient samples. Monosodium iodoacetate was injected unilaterally into the knees of male and female wild-type (WT) and muMT mice (lacking B cells) to induce articular cartilage damage. Repeated nociceptive behavioral testing was performed, and serum was collected for antibody isolation and passive transfer experiments. Serum antibodies collected from patients with OA were tested in MIA-treated muMT mice. Biochemical analyses were performed on knee joint tissues. Monosodium iodoacetate-treated WT mice developed chronic ipsilateral hindlimb allodynia, hyperalgesia, and unweighting, but these pain behaviors were absent in MIA-treated muMT mice, indicating that cartilage injury-induced pain is B-cell dependent. IgM accumulation was observed in the knee tissues of MIA-treated mice, and intra-articular injection of IgM from MIA-treated mice into MIA-treated muMT mice caused nociceptive sensitization. Similarly, intra-articular injection of IgM from patients with OA was pronociceptive in muMT MIA mice and control subject IgM had no effect. Monosodium iodoacetate-injected joints demonstrate elevated levels of complement component 5a (C5a) and C5a receptor blockade using intra-articular PMX-53-reduced sensitization. These data suggest that MIA-treated mice and patients with OA generate pronociceptive antibodies, and further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain.

Abstract: Temporomandibular disorder (TMD) is the most prevalent painful condition in the craniofacial area. Recent studies have suggested that external or intrinsic trauma to the temporomandibular joint (TMJ) is associated with the onset of painful TMD in patients. Here, we investigated the effects of TMJ trauma through forced-mouth opening (FMO) in mice to determine pain behaviors and peripheral sensitization of trigeminal nociceptors in both sexes. Forced-mouth opening increased mechanical pain as assessed by the von Frey test, with spontaneous pain-like behaviors assessed using the mouse grimace scale and anxiety-like behaviors assessed using the open-field test. Changes in pain-like behaviors were not different between male and female mice. However, in vivo GCaMP Ca2+ imaging of intact trigeminal ganglia (TG) showed modality- and sex-dependent changes. Forced-mouth opening increased spontaneous Ca2+ responses and mechanical hypersensitivity of TG neurons compared to the sham group, which was more pronounced in male mice. Forced-mouth opening also increased Ca2+ responses evoked by cold, heat, and capsaicin stimuli, which was not different between the sexes. In retrogradely labeled trigeminal TMJ afferents, FMO induced an increase in small-sized neuronal proportions with increased colocalization with calcitonin gene-related peptides and transient receptor potential vanilloid subtype 1, which was modestly sex dependent. These results suggest that TMJ injury leads to persistent posttraumatic hyperalgesia associated with peripheral sensitization of trigeminal nociceptors with distinct sex dependency.

Abstract: Chronic pain is a pervasive, disabling, and understudied feature of multiple sclerosis (MS), a progressive demyelinating and neurodegenerative disease. Current focus on motor components of MS disability combined with difficulties assessing pain symptoms present a challenge for the evaluation and management of pain in MS, highlighting the need for novel methods of assessment of neural signatures of chronic pain in MS. We investigate chronic pain in MS using MS-related trigeminal neuralgia (MS-TN) as a model condition focusing on gray matter structures as predictors of chronic pain. T1 imaging data from people with MS (n = 75) and MS-TN (n = 77) using machine learning (ML) was analyzed to derive imaging predictors at the level of cortex and subcortical gray matter. The ML classifier compared imaging metrics of patients with MS and MS-TN and distinguished between these conditions with 93.4% individual average testing accuracy. Structures within default-mode, somatomotor, salience, and visual networks (including hippocampus, primary somatosensory cortex, occipital cortex, and thalamic subnuclei) were identified as significant imaging predictors of trigeminal neuralgia pain. Our results emphasize the multifaceted nature of chronic pain and demonstrate the utility of imaging and ML in assessing and understanding MS-TN with greater objectivity.