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Morphine and other opioids are commonly used to treat pain despite their numerous adverse side effects. Modulating μ-opioid receptor (MOR) signaling is one way to potentially improve opioid therapy. In mice, the chaperone protein Hsp90 mediates MOR signaling within the brain. Here, we found that inhibiting Hsp90 specifically in the spinal cord enhanced the antinociceptive effects of morphine in mice. Intrathecal, but not systemic, administration of the Hsp90 inhibitors 17-AAG or KU-32 amplified the effects of morphine in suppressing sensitivity to both thermal and mechanical stimuli in mice. Hsp90 inhibition enabled opioid-induced phosphorylation of the kinase ERK and increased abundance of the kinase RSK in the dorsal horns of the spinal cord, which are heavily populated with primary afferent sensory neurons. The additive effects of Hsp90 inhibition were abolished upon intrathecal inhibition of ERK, RSK, or protein synthesis. This mechanism downstream of MOR, localized to the spinal cord and repressed by Hsp90, may potentially be used to enhance the efficacy and presumably decrease the side effects of opioid therapy.
Learn More >Objectives The link between social support and physical activity has primarily been examined cross-sectionally, with a focus on the direct association between the two variables. In a distinct body of work, there has been growing interest in the role of social support in reducing pain (emotional and physical). We examined the relationship between social support and physical activity over time. We further examined whether reduced pain mediates the relationship between social support and physical activity. Design Data were drawn from Waves 15, 16, and 17 of the Household Income and Labour Dynamics in Australia survey. Methods Mediation models were used to test our hypotheses in (a) a representative sample of 12,517 people residing in Australia, and (b) a subsample of 927 people with a condition that causes chronic or recurring pain. Results Social support was a weak predictor of subsequent physical activity in both the full sample and the subsample of people with a condition that causes chronic or recurring pain. However, in both samples, mediation analyses demonstrated a significant indirect effect of social support on physical activity through reduced pain. Conclusions One pathway through which social support impacts physical activity is by reducing peoples' pain. Increasing and strengthening peoples' social support networks may confer benefits for their physical activity levels, including among those whose physical activity is limited by pain. Statement of contribution What is already known on this subject? Social support can have a positive effect on health behaviours, including physical activity. There is somewhat inconsistent evidence for a positive direct relationship between social support and physical activity. Pain can be a barrier to physical activity, but may be attenuated by social support. What does this study add? Social support affected physical activity indirectly by reducing peoples' pain. This was true for both the general population and a subsample with a chronic pain condition. Improving peoples' social support networks may confer benefits for their physical activity.
Learn More >Migraine is associated with debilitating symptoms that can affect daily functioning. "My Migraine Voice" was a large, cross-sectional, multi-country online survey aimed at understanding disease burden directly from people with migraine.
Learn More >Voltage gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic SAR studies carried out to identify novel sulfonamide derivatives as potent, selective and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5 and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43 and 51 have shown favorable PK profile across different species and robust efficacy in veratridine and formalin induced inflammatory pain models in mice. Compound 51 has also shown significant effect in CCI induced neuropathic pain model. Profile of 51 has indicated that it has the potential for further evaluation as a therapeutic for pain.
Learn More >The evidence that action shapes perception has become widely accepted, for example, in the domain of vision. However, the manner in which action-relevant factors might influence the neural dynamics of acute pain processing has remained underexplored, particularly the functional roles of anterior insula (AI) and midanterior cingulate cortex (mid-ACC), which are frequently implicated in acute pain. To address this, we examined a unique group of heterozygous carriers of the rare R221W mutation on the nerve growth factor (NGF) gene. R221W carriers show a congenitally reduced density of C-nociceptor afferent nerves in the periphery, but can nonetheless distinguish between painful and nonpainful stimulations. Despite this, carriers display a tendency to underreact to acute pain behaviorally, thus exposing a potential functional gap in the pain-action relationship and allowing closer investigation of how the brain integrates pain and action information. Heterozygous R221W carriers and matched controls performed a functional magnetic resonance imaging (fMRI) task designed to dissociate stimulus type (painful or innocuous) from current behavioral relevance (relevant or irrelevant), by instructing participants to either press or refrain from pressing a button during thermal stimulation. Carriers' subjective pain thresholds did not differ from controls', but the carrier group showed decreased task accuracy. Hemodynamic activation in AI covaried with task performance, revealing a functional role in pain-action integration with increased responses for task-relevant painful stimulation ("signal," requiring button-press execution) over task-irrelevant stimulation ("noise," requiring button-press suppression). As predicted, mid-ACC activation was associated with action execution regardless of pain. Functional connectivity between AI and mid-ACC increased as a function of reported urge to withdraw from the stimulus, suggesting a joint role for these regions in motivated action during pain. The carrier group showed greater activation of primary sensorimotor cortices-but not the AI and mid-ACC regions-during pain and action, suggesting compensatory processing. These findings indicate a critical role for the AI-mid-ACC axis in supporting a flexible, adaptive action selection during pain, alongside the accompanying subjective experience of an urge to escape the pain.
Learn More >The ongoing substance misuse epidemic in the United States is complex and dynamic and should be approached as such in the development and evaluation of policy. Drug overdose deaths (largely attributable to opioid misuse) in the United States have grown exponentially for almost four decades, but the mechanisms of this growth are poorly understood. From analysis of 661,565 overdose deaths from 1999 to 2017, we show that the age-specific drug overdose mortality curve for each birth-year cohort rises and falls according to a Gaussian-shaped curve. The ascending portion of each successive birth-year cohort mortality curve is accelerated compared with that of all preceding birth-year cohorts. This acceleration can be attributed to either of two distinct processes: a stable peak age, with an increasing amplitude of mortality rate curves from one birth-year cohort to the next; or a youthward shift in the peak age of the mortality rate curves. The overdose epidemic emerged and increased in amplitude among the 1945-1964 cohort (Baby Boomers), shifted youthward among the 1965-1980 cohort (Generation X), and then resumed the pattern of increasing amplitude in the 1981-1990 Millennials. These shifting age and generational patterns are likely to be driven by socioeconomic factors and drug availability, the understanding of which is important for the development of effective overdose prevention measures.
Learn More >Fully illuminating mechanisms relating parent behaviors to child pain require examining both verbal and nonverbal communication. We conducted a multimethod investigation into parent nonverbal communication and physiology, and investigated the psychometric properties of the Scheme for Understanding Parent Emotive Responses Scale to assess parent nonverbals accompanying reassurance and distraction. 23 children (7-12 years) completed the cold pressor task with their parent (predominately mothers). Parent heart rate and heart rate variability were monitored and assessed. The Scheme for Understanding Parent Emotive Responses Scale coding of parent nonverbal behaviors (i.e., vocal cues, facial expressions, posture) was used to detect levels of fear, warmth, disengagement and humor. : Preliminary evidence for the psychometric properties of the scale are offered. Parent reassurance was associated with more fear, less warmth and less humor compared with distraction.
Learn More >The crosstalk between the immune and nervous system in the regulation of OA pain is increasingly becoming evident. GM-CSF signals in both systems and might be a new treatment target to control OA pain. Anti GM-CSF treatment has analgesic effects in OA without affecting synovitis scores, suggesting that treatment effects are not caused by local anti-inflammatory effects. We aimed to evaluate whether expression of GM-CSF and its receptor GM-CSFrα in synovial tissue is linked to synovial inflammation and/or knee pain in knee OA patients.
Learn More >Alcohol use has been associated with opioid misuse and dependence among adults with chronic pain. Yet, mechanisms underlying the relation between alcohol use problems and opioid misuse and dependence have yet to be fully explored among this population. Distress tolerance, reflecting the perceived ability to withstand negative emotional states, has demonstrated independent associations with alcohol use problems and opioid misuse, but these associations have not been explored among persons with chronic pain. The present study examined the moderating role of distress tolerance in terms of the association between alcohol use problems with opioid misuse and severity of opioid dependence. Participants included 424 adults (74.1% female; = 38.3, = 11.1) reporting current chronic pain and opioid medication use. Results indicated that alcohol use problems were significantly associated with current opioid misuse ( = 0.54, < .001) and severity of opioid dependence ( = 0.08, = .002) only for those with lower distress tolerance. These findings suggest that among individuals with chronic pain, the association between alcohol use problems and opioid misuse as well as opioid dependence severity is amplified among those with lower perceived distress tolerance. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Pain is one of the most common reasons to seek medical attention and chronic pain is a worldwide epidemic. There are currently no relevant biomarkers for the diagnosis of chronic pain, and new therapeutic strategies for chronic pain treatment are desperately needed. The chronic constriction injury (CCI) of the sciatic nerve is a widely used preclinical model of pathological neuropathic pain. Over the past decade, investigators have come to appreciate the many contributions of noncoding RNA including microRNA (miRNA), and other long and short noncoding (nc) RNAs. The development and/or maintenance of chronic pain could be controlled epigenetically through ncRNAs. Here we seek to characterize CNS tissues in a mouse model of neuropathic pain as this may serve to elucidate potential biomarkers relevant to pathological pain in humans. Male C57BL6/J mice (6 CCI and 6 sham procedure) underwent surgery for sciatic nerve ligation with chromic gut sutures. Following 7 days, mechanical allodynia was quantified using the von Frey assay. Mice were then euthanized for collection of spinal cord and sciatic nerve. cDNA was synthesized to 627 unique mature miRNAs from the total RNA. In the CCI mice that displayed mechanical allodynia, 11 and 125 miRNAs were differentially expressed (i.e., greater than 1.5-fold increase or decrease; P < 0.05) in the spinal cord and sciatic nerve, respectively, as compared to sham controls. Among those differentially expressed miRNAs in the sciatic nerve of CCI mice, the following passed the more stringent Bonfferoni correction: miR-138-3p, miR-138-5p and miR-676-3p, reduced and miR-142-5p, increased. Our data support miRNAs as promising therapeutic targets for the treatment of pathological pain.
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