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The protease activated receptor (PAR) family is a group of G-protein coupled receptors (GPCRs) activated by proteolytic cleavage of the extracellular domain. PARs are expressed in a variety of cell types with crucial roles in hemostasis, immune responses, inflammation, and pain. PAR3 is the least researched of the four PARs, with little known about its expression and function. We sought to better understand its potential function in the peripheral sensory nervous system. Mouse single-cell RNA sequencing data demonstrates that PAR3 is widely expressed in dorsal root ganglion (DRG) neurons. Co-expression of PAR3 mRNA with other PARs was identified in various DRG neuron subpopulations, consistent with its proposed role as a coreceptor of other PARs. We developed a lipid tethered PAR3 agonist, C660, that selectively activates PAR3 by eliciting a Ca response in DRG and trigeminal (TG) neurons. In vivo, C660 induces mechanical hypersensitivity and facial grimacing in WT but not PAR3 mice. We characterized other nociceptive phenotypes in PAR3 mice and found a loss of hyperalgesic priming in response to IL-6, carrageenan, and a PAR2 agonist, suggesting that PAR3 contributes to long-lasting nociceptor plasticity in some contexts. To examine the potential role of PAR3 in regulating the activity of other PARs in sensory neurons, we administered PAR1, PAR2, and PAR4 agonists and assessed mechanical and affective pain behaviors in WT and PAR3 mice. We observed that the nociceptive effects of PAR1 agonists were potentiated in the absence of PAR3. Our findings suggest a complex role of PAR3 in the physiology and plasticity of nociceptors. Perspective: We evaluated the role of PAR3, a G-protein coupled receptor, in nociception by developing a selective peptide agonist. Our findings suggest that PAR3 contributes to nociception in various contexts and plays a role in modulating the activity of other PARs.
Learn More >Anxiety is often comorbid with pain. Delta opioid receptors (DORs) are promising targets for the treatment of pain and mental disorders with little addictive potential. However, their roles in anxiety symptoms at different stages of pain are unclear. In the current study, mice with inflammatory pain at the 4th hour following complete Freund's adjuvant (CFA) injection displayed significant anxiety-like behavior, which disappeared at the 7th day. Combining electrophysiology, optogenetics, and pharmacology, we found that activation of delta opioid receptor 1 (DOR1) in the central nucleus amygdala (CeA) inhibited both the anxiolytic excitatory input from the basolateral amygdala (BLA) and the anxiogenic excitatory input from the parabrachial nucleus (PBN). In contrast, activation of delta opioid receptor 2 (DOR2) did not affect CeA excitatory synaptic transmission in normal and 4-hour CFA mice but inhibited the excitatory projection from the PBN rather than the BLA in 7-day CFA mice. Furthermore, the function of both DOR1 and DOR2 was downregulated to the point of not being detectable in the CeA of mice at the 21st day following CFA injection. Taken together, these results suggest that functional switching of DOR1 and DOR2 is associated with anxiety states at different stages of pain via modulating the activity of specific pathways (BLA-CeA and PBN-CeA).
Learn More >Approximately 20% of knee osteoarthritis patients undergoing total knee arthroplasty (TKA) report chronic postoperative pain. Studies suggest that preoperative variables such as impaired descending pain control, catastrophizing, function, and neuropathic pain-like symptoms may predict postoperative pain 12 months after TKA, but the combined prediction value of these factors has not been tested. The current prospective cohort study aimed to combine preoperative risk factors to investigate the predictive value for postoperative pain 12 months after TKA.
Learn More >Limited evidence exists exploring perceptions of which aspects of a pain management program are perceived as valuable and impactful. The aim of this study was to explore patient beliefs about which aspects of a pain management program were valued and/or had perceived impact. One-on-one structured interviews were conducted with 11 adults three months after their completion of the Spark Pain Program at Westmead Hospital, Sydney, Australia. Concepts in the transcripts were inductively identified and explored, utilizing thematic analysis to better understand their relevance to the study aim. : Four themes emerged: (1) "The program overall was positive, but…"; (2) "I valued my improved knowledge and understanding of pain, but…"; (3) "I valued the stretching/relaxation/pacing/activity monitoring"; and (4) "I valued being part of a supportive and understanding group". Participants reported that they liked being treated as an individual within the group. A lack of perceived personal relevance of key messages was identified in some participants; it appears that patients in pain programs must determine that changes in knowledge, beliefs, and attitudes are personally relevant in order for the changes to have a significant impact on them. This study provides new insights into aspects of a pain management program that were perceived as valuable and impactful, areas that "missed the mark", and hypotheses to guide the implementation of service delivery and program redesign.
Learn More >To characterize suicidality among youth with juvenile fibromyalgia syndrome (JFMS) receiving treatment from pediatric rheumatologists at a tertiary care center in order to determine the prevalence of suicidality in JFMS and to explore risk factors for persistent suicidal ideation.
Learn More >Opioid use and chronic pain are prevalent in the veteran population. Collaborative Care enhances coordination between patients and their care teams and Motivational Interviewing (MI) is a communication style designed to facilitate behavior change. This study evaluated the use of Collaborative Care with MI (CCMI) with patients with chronic pain and high-risk prescription opioid use.
Learn More >Chronic pain is associated with significant physical and psychological impairments across the adult lifespan. However, there is a relative gap in knowledge on individual differences that predict pain-related functioning. The current study highlights one important source of individual variation: age.
Learn More >Biased interpretations of ambiguous bodily threat situations characterise youth with chronic pain, and have been associated with functional disability for this population. Despite predictions by the fear-avoidance model of chronic pain, that fear and avoidance of pain explain the association between threat perceptions and disability, this has not yet been explored in youth with chronic pain. The current study aimed to address this gap by investigating these proposed relationships, in addition to the association between bodily threat interpretations and daily aspects of disability (as well as social, and emotional impairments).
Learn More >Pain and depression are episodic conditions that might take a chronic course. They are clearly related, but information on how they influence each other in the process of chronification is limited. Pain catastrophizing is hypothesized to play a role in the development of depression and chronic pain, but few longitudinal studies have investigated their association over a longer-term. In this study, a random cohort from the general population (n = 4764) answered questions about pain, catastrophizing, and depression at five assessments in yearly intervals. Linear mixed models showed that within persons, increases in pain intensity and catastrophizing were independently associated with increases in depressive symptoms (mean change = -1.12, 95% CI [-1.32, -0.91]) and -1.29, 95% CI [-1.52, -1.05], respectively). In prospective analyses restricted to individuals without depression above cut-off at baseline, chronic pain increased the risk of endorsing depression over the following four years (OR =2.01, 95% CI [1.71, 2.37]). Seven percent showed a chronic course of depression, as indicated by scores above cut-off on at least three of five assessments. Number of years lived with chronic pain was associated with a chronic course of depression, with odds ratios increasing from 1.55 (95% CI [0.87, 2.91]) to 14.19 (95% CI [8.99, 22.41]) when reporting chronic pain on two versus five assessments compared to none. The results suggest that when pain intensity or catastrophizing change, depressive symptoms change in the same direction. When pain and catastrophizing become chronic, they appear to be mutually reinforcing determinants for chronic depression.
Learn More >Pain puts patients at risk for developing psychiatric conditions such as anxiety and depression. Pre-clinical mouse models of pain-induced affective behavior vary widely in methodology and results, impairing progress towards improved therapeutics. To systematically investigate the effect of long-term inflammatory pain on exploratory behavior and stress coping strategy, we assessed male C57BL/6J mice in the forced swim test (FST), elevated zero maze (EZM), and open field test (OFT) at four and six weeks post-injection of Complete Freund's Adjuvant (CFA), while controlling for testing order and combination. Inflammatory pain did not induce a passive stress coping strategy in the FST and did not reduce exploratory behavior in the EZM or the OFT. Using systematic correlational analysis and composite behavioral scores, we found no consistent association among measures for mice with or without inflammatory pain. A meta-analysis of similar studies indicated a modest, significant effect of CFA on exploratory behavior, but not immobility in the FST, and high heterogeneity among effect sizes in all three paradigms. Given the urgency for understanding the mechanisms of pain comorbidities and identifying novel therapies, these findings support the reallocation of our limited resources away from such unreliable assays and toward motivated and naturalistic behaviors. Future studies in pain and psychiatric translational research may benefit by considering outcomes beyond binary categorization, quantifying the associations between multiple measured behaviors, and agnostically identifying subtle yet meaningful patterns in behaviors.
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