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There is strong evidence showing that the activation of peripheral proteinase-activated receptors type 2 (PAR-2) can initiate hyperalgesic and inflammatory responses in the joint. However, to date, there is no report of functional spinal PAR-2 receptors in arthritis models. The primary aim of this study was to evaluate the activity of PAR-2 receptors at the spinal cord by using a potent agonist (FLIGRL) in naïve animals, and an antagonist (GB83) in different models of joint pain. Saline or FLIGRL (10 nmol) were injected intrathecally in naïve animals and nociceptive behaviour was evaluated over a 24 h time period by von Frey hair algesiometry. Paw withdrawal threshold decreased from 3 to 24 h and this allodynic effect was blocked by GB83 (90 nmol; i.p.). Acute inflammatory joint pain was induced by injecting 0.5% kaolin/carrageenan (50 μL each) into the right knee joint of male Wistar rats (24 hr recovery). Chronic inflammatory joint pain was modelled by intraarticular injection of Freund's complete adjuvant (FCA; 50 μL; 7 days recovery) or chronic osteoarthritis pain by sodium monoiodoacetate (MIA; 3 mg; 14 days recovery). Animals were then treated with either intrathecal vehicle or 10 nmol of GB83 (10 μL); joint pain was evaluated throughout the subsequent 3 h period. The acute inflammatory pain induced by kaolin/carrageenan was not affected by treatment with GB83. Conversely, both chronic arthritis models demonstrated increased hind paw withdrawal threshold after spinal injection of the PAR-2 antagonist. Based on these results, spinal PAR-2 receptors are involved in joint nociceptive processing in chronic but not acute arthritic conditions.
Learn More >The increased use of opioids to treat pain has led to a dramatic increase in opioid abuse. Our previous data indicate that pain may facilitate the development of opioid abuse by increasing the magnitude and duration of opioid withdrawal. The present study tested the hypothesis that social housing would facilitate recovery of activity depressed by pain and opioid withdrawal. Male Sprague Dawley rats were housed either in pairs or alone and then moved to a cage with a running wheel for 6 hrs daily to assess pain- and opioid withdrawal-induced depression of wheel running. Rats were implanted with two morphine (75 mg each) or placebo pellets to induce opioid dependence and were simultaneously injected with Complete Freund's Adjuvant or saline into the right hind paw to induce persistent inflammatory pain. Hind paw inflammation depressed wheel running whether rats were implanted with a morphine or placebo pellet. Pair-housed rats showed greater recovery of wheel running than individually housed rats. Spontaneous morphine withdrawal precipitated by removal of the morphine pellets caused a reduction in wheel running that was greater in rats with hind paw inflammation compared to pain free rats. Social housing facilitated recovery from withdrawal in rats with hind paw inflammation, but slowed recovery in pain free rats. These data suggest that social housing facilitates recovery by reducing pain both before and during opioid withdrawal. Our findings are consistent with previous studies showing that social buffering reduces pain-evoked responses.
Learn More >Given the role of Ca3.2 isoform among T-type Ca channels (T-channels) in somatic and visceral nociceptive processing, we analyzed the contribution of Ca3.2 to butyrate-induced colonic pain and nociceptor hypersensitivity in mice, to evaluate whether Ca3.2 could serve as a target for treatment of visceral pain in irritable bowel syndrome (IBS) patients. Mice of ddY strain, and wild-type and Ca3.2-knockout mice of a C57BL/6J background received intracolonic administration of butyrate twice a day for 3 days. Referred hyperalgesia in the lower abdomen was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load or chemicals was evaluated by counting nociceptive behaviors. Spinal phosphorylated ERK was detected by immunohistochemistry. Ca3.2 knockdown was accomplished by intrathecal injection of antisense oligodeoxynucleotides. Butyrate treatment caused referred hyperalgesia and colonic hypersensitivity to distension in ddY mice, which was abolished by T-channel blockers and/or Ca3.2 knockdown. Butyrate also increased the number of spinal phosphorylated ERK-positive neurons following colonic distension in the anesthetized ddY mice. The butyrate-treated ddY mice also exhibited T-channel-dependent colonic hypersensitivity to intracolonic NaS, known to enhance Ca3.2 activity, and TRPV1, TRPA1 or proteinase-activated receptor 2 (PAR2) agonists. Wild-type, but not Ca3.2-knockout, mice of a C57BL/6J background, after treated with butyrate, mimicked the T-channel-dependent referred hyperalgesia and colonic hypersensitivity in butyrate-treated ddY mice. Our study provides definitive evidence for an essential role of Ca3.2 in the butyrate-induced colonic pain and nociceptor hypersensitivity, which might serve as a target for treatment of visceral pain in IBS patients.
Learn More >The fear-avoidance model of chronic pain predicts that catastrophic (mis)interpretation of pain elicits pain-related fear that in turn may spur avoidance behaviour leading to chronic pain disability. Here we investigated whether performing a movement to avoid a painful stimulus in the context of a novel movement increases threat and pain-related fear towards this novel movement, and whether avoidance behaviour persisted when given the choice between performing the acquired movement to avoid a painful stimulus or an alternative, novel movement. Applying a robotic arm-reaching task, participants could choose between two movements to reach a target location: a short, but painful movement trajectory, or a longer non-painful movement trajectory. After avoidance acquisition, the option to choose the painful trajectory was removed. The Experimental Group (N=50) could choose between the longest trajectory or a novel intermediate trajectory, whereas the Control Group (N=50) was allowed to only perform the novel trajectory. In a final test, participants of both groups were allowed to choose any of the three trajectories. Post-acquisition, Experimental Group participants showed elevated pain-expectancy and pain-related fear towards the novel trajectory, compared to the Control Group. During test, the Experimental Group participants persisted in performing the longest pain-free (avoidance) trajectory, and were less likely to choose the novel trajectory. In addition, these participants maintained higher levels of pain-related fear for the novel trajectory compared to the Control Group. These findings suggest that avoidance in the context of other neutral activities/movements may lead to the development and maintenance of threat appraisals and irrational fears.
Learn More >Surgical procedures are necessary in up to 50% of trigeminal neuralgia (TN) patients. While radiofrequency (RF) is more widely used, it is associated with high intra-procedural costs and long technical learning time. Other simpler procedures such as balloon compression (BC) require a lower training period and have significant lower costs. We evaluated the effects of BC and RF in pain control in primary TN in a randomized, double-blinded, head-to-head trial. Individuals were randomly allocated in one of two groups: BC and RF. Throughout pain, psychological and quality of life measurements were performed at baseline and after surgery. The main outcome was the worst pain in the last 24 hours (0-10) at six months postoperatively. After the inclusion of half of the estimated sample, a pre-planned interim analysis was performed when thirty-three patients (62.1 ± 9.4 y.) completed the study. Pain intensity (CI95% 0.6-3.8, and -0.6-2.2, for BC and RF) did not significantly differ. Complications, interference of pain in daily life (CI95% -0.1-2.3 and -0.4-2.3, for BC and RF), neuropathic pain symptoms (CI95% 1.7-3.6 and 3.0-5.7, for BC and RF), mood (CI95% 4.8-11.5 and 5.5-15.1, BC and RF, respectively), medication use and quality of life (CI95% 80.4-93.1 and 83.9-94.2, for BC and RF) were also not different. RF presented more paresthetic symptoms than BC at 30 days following intervention. Based on these results, the study was halted due to futility as BC was not superior do RF.
Learn More >Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase-like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling. ROR2 was up-regulated in the cartilage in response to inflammatory cytokines and mechanical stress. The main ligand for ROR2, WNT5A, and the targets YAP and connective tissue growth factor were up-regulated in osteoarthritis in humans. In vitro, ROR2 overexpression inhibited chondrocytic differentiation. Conversely, ROR2 blockade triggered chondrogenic differentiation of C3H10T/ cells and suppressed the expression of the cartilage-degrading enzymes a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5. The chondrogenic effect of ROR2 blockade in the cartilage was independent of WNT signaling and was mediated by down-regulation of YAP signaling. ROR2 signaling induced G protein and Rho-dependent nuclear accumulation of YAP, and YAP inhibition was required but not sufficient for ROR2 blockade-induced chondrogenesis. ROR2 silencing protected mice from instability-induced osteoarthritis with improved structural outcomes, sustained pain relief, and without apparent side effects or organ toxicity. Last, ROR2 silencing in human articular chondrocytes transplanted in nude mice led to the formation of cartilage organoids with more and better differentiated extracellular matrix, suggesting that the anabolic effect of ROR2 blockade is conserved in humans. Thus, ROR2 blockade is efficacious and well tolerated in preclinical animal models of osteoarthritis.
Learn More >Persistent post-surgical pain is common among patients undergoing surgery, is detrimental to patients' quality of life, and can precipitate long-term opioid use. The purpose of this randomized controlled trial is to assess the effects of a behavioral intervention offered prior to surgery for patients at risk for poor post-surgical outcomes, including persistent pain and impaired functioning.
Learn More >Pain assessment that fully represents patients' pain experiences is essential for chronic pain research and management. The traditional primary outcome measure has been a patient's average pain intensity over a time period. In this series of three articles, we examine whether pain assessment can be enhanced by considering additional outcome measures capturing temporal aspects of pain, such as pain maxima, duration, and variability. Ecological momentary assessment (EMA) makes the assessment of such indices readily available. In this first article, we discuss the rationale for considering additional pain indices derived from EMA and examine which are most important to stakeholders. Patients (n=32), clinicians (n=20), and clinical trialists (n=20) were interviewed about their preference rankings for Average, Worst, and Least Pain, Time in High Pain, Time in No/Low Pain, Pain Variability, and Pain Unpredictability. Each stakeholder group displayed a distinct preference hierarchy for different indices, and there were few commonalities between groups. Patients favored Worst Pain and Time in High Pain, followed by Pain Variability and Unpredictability. Trialists favored Average Pain, whereas clinicians favored Worst Pain. Results suggest that multiple temporal aspects of pain are relevant for stakeholders and should be considered when evaluating the efficacy of pain management. PERSPECTIVE: Examining which aspects of pain are most important to measure from the perspective of different stakeholders can facilitate efforts to include all relevant treatment outcomes. Our study suggests that multiple temporal aspects of pain intensity are important to stakeholders. This should be considered when evaluating the efficacy of pain management.
Learn More >Back pain is linked to intervertebral disc (IVD) degeneration, but clinical studies show the relationship is complex. This study assessed whether males and females have distinct relationships between IVD degeneration and pain using an in vivo rat model. Forty-eight male and female Sprague-Dawley rats had lumbar IVD puncture or sham surgery. Six weeks after surgery, IVDs were evaluated by radiologic IVD height, histological grading, and biomechanical testing. Pain was assessed by von Frey assay and dorsal root ganglia (DRG) expression of Calca and Tac1 genes. Network analysis visualized which measures of IVD degeneration most related to pain by sex. In both females and males, annular puncture induced structural IVD degeneration, but functional biomechanical properties were similar to sham. Females and males had distinct differences in mechanical allodynia and DRG gene expression, even though sex differences in IVD measurements were limited. Network analysis also differed by sex, with more associations between annular puncture injury and pain in the male network. Sex differences exist in the interactions between IVD degeneration and pain. Limited correlation between measures of pain and IVD degeneration highlights the need to evaluate pain or nociception in IVD degeneration models to better understand nervous system involvement in discogenic pain.
Learn More >To describe how chronic low back pain (CLBP) impacts on utility scores and which patients' characteristics most affect these scores in the province of Quebec.
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