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To establish the prevalence of long-term and serious harms of medical cannabis for chronic pain.
Learn More >Pain is a common outcome after lower extremity fracture requiring surgical fixation (LEF). Although psychosocial characteristics have meaningful associations with adverse outcomes, no studies have evaluated how psychosocial characteristics throughout recovery are associated with pain outcomes. The primary purpose of this study was to determine whether psychosocial characteristics are early risk factors for pain outcomes in patients following LEF who have no history of chronic pain.
Learn More >Immunoglobulins (IG) are widely used for the treatment of a variety of immune-mediated diseases. The exact mechanism of action remains unknown, but IG modulate the expression and function of Fc receptors, interfere with complement activation and production of cytokines, neutralize pathogenic autoantibodies, and affect the activation and effector functions of B and T lymphocytes. Immunoglobulins are usually delivered intravenously, and are effective in ameliorating motor symptoms, and/or preventing disease progression in immune-mediated neuropathies, including Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.
Learn More >Symptoms of people who have systemic sclerosis (SSc) are heterogeneous and difficult to address clinically. Because diverse symptoms often co-occur and may share common underlying mechanisms, identifying symptoms that cluster together may better target treatment approaches. We sought to identify and characterize patient subgroups based on symptom experience.
Learn More >Psoriatic arthritis (PsA) is a chronic inflammatory disease that reduces quality of life. This study assessed the effects of risankizumab (RZB) on the achievement of minimal clinically important differences (MCID) in patient-reported outcomes (PROs).
Learn More >Assessment of the severity of pruritus is difficult in cats, because they manifest discomfort by increased licking, increased scratching or both.
Learn More >Persistent pain despite satisfactory disease treatment is frequent in rheumatoid arthritis (RA) and spondyloarthritis (Spa) and may result from specific changes in central pain processing. We assessed these mechanisms further, by systematically comparing thermal pain thresholds and conditioned pain modulation (CPM) between patients with active RA or Spa and healthy controls.We included 50 RA and 50 Spa patients and 100 age- and sex-matched controls. Heat and cold pain thresholds (HPT-CPT) were measured on the dominant forearm, and CPM was assessed by applying conditioning stimuli (immersion in a cold water bath) to one foot and the non-dominant hand in two successive randomized sequences. Descending pain modulation was assessed as the difference in HPT (in °C) before and after conditioning. Larger HPT differences (i.e. a larger CPM effect) reflected more efficient descending inhibition. Potential associations between changes in CPM and clinical data, including disease activity, pain intensity, psychological and functional variables, were systematically assessed.HPT and CPT were similar in patients and controls. Mean CPM effect was significantly weaker in patients than controls for conditioning applied to either the foot (0.25°C ±2.57 vs. 2.79°C ±2.31; p<0.001) or the non-dominant hand (0.57°C ±2.74 vs. 2.68°C ±2.12; p<0.001).The smaller CPM effect in patients was correlated with average pain intensity, but not with disease activity or other clinical characteristics, suggesting a significant pathophysiological role for changes in endogenous pain modulation in the mechanisms of chronic pain associated with inflammatory rheumatism.
Learn More >Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABA in NaV1.8-positive sensory neurons (;) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABA. Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABA and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I-V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund's adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8 afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABA in NaV1.8 nociceptors constitutes an "open gate" pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits.
Learn More >(1) Background: The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods: The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results: intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 1:1 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THC:CBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions: these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain.
Learn More >Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Current AF antiarrhythmic drugs have limited efficacy and carry the risk of ventricular pro-arrhythmia. GsMTx4, a mechanosensitive channel (MSC)-selective inhibitor, has been shown to suppress arrhythmias through the inhibition of stretch-activated channels (SACs) in the heart. The cost of synthesizing this peptide is a major obstacle to clinical use. Here, we studied two types of short peptides derived from GsMTx4 for their effects on a stretch-activated big potassium (BK) channel (SAKcaC) from the heart. Type I, a 17-residue peptide (referred to as Pept 01), showed comparable efficacy, whereas type II (i.e. Pept 02), a 10-residue peptide, exerted even more potent inhibitory efficacy on SAKcaC compared to GsMTx4. We identified through mutagenesis important sequences required for peptide functions. Additionally, molecular dynamics (MD) simulations revealed common structural features with a hydrophobic head followed by a positively charged protrusion that may be involved in peptide-channel/lipid interactions. Furthermore, we suggest that these short peptides may inhibit SAKcaC through a specific modification to the mechano-gate, as the inhibitory effects for both types of peptides were mostly abolished when tested with a mechano-insensitive channel variant (STREX-del) and a non-mechanosensitive BK (mSlo1) channel. These findings may offer an opportunity for the development of a new class of drugs in the treatment of cardiac arrhythmia generated by excitatory SACs in the heart..
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