Browse by Audience
The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion specific manner. However, it is unknown how mu-opioid signalling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in-vitro patch clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist, DAMGO produced a concentration-dependant inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long-lasting and not reversed upon washout of DAMGO, or by application of the mu-opioid receptor antagonist, CTAP, suggesting an inhibitory long-term depression (iLTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/PKA signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Taken together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.Considering that both the OFC and the opioid system regulate reward, motivation, and food intake; understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Secondly, mu-opioids recruit PV+ inputs to suppress inhibitory synaptic transmission in the mOFC. Thirdly, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.
The prevalence and intensity of persistent post-surgical pain (PPSP) after breast cancer surgery are uncertain. We conducted a systematic review and meta-analysis to further elucidate this issue.
Cognitive Functional Therapy (CFT) is a physiotherapist-led individualised intervention for people with people with non-specific chronic low back pain (CLBP), involving biopsychosocial pain education, graded movement exposure and lifestyle coaching. A multicentre randomised controlled trial (RCT), including 206 participants with CLBP in Ireland, supported CFT's effectiveness for reducing disability, but not pain, compared to a group exercise and education intervention. In this study, causal mediation analysis was used to determine whether the effect of CFT on disability and the lack of effect on pain (relative to a group exercise and education intervention) is mediated by certain psychological and lifestyle factors. Hypothesised mediators measured were pain self-efficacy, stress, fear of physical activity, coping, depression, anxiety, and sleep, at 6 months. The outcomes measured were functional disability and pain intensity at 12 months. This causal mediation study shows that the majority of benefit of CFT (relative to a group exercise and education intervention) for disability is due to increasing pain self-efficacy. CFT did not improve the majority of the hypothesised mediators (stress, fear of physical activity, coping, depression, anxiety and sleep) and these mediators were not associated with either disability or pain. Unfortunately, the proportion of missing data in this study is substantial and these findings can only be considered hypothesis-generating. Therefore, future research should examine replicating the results of this study to verify the role of self-efficacy and other proposed mediators (e.g. stress, coping, sleep, fear) on clinical outcomes.
To examine trends in the initial prescription of commonly-prescribed analgesics and patient- as well as practice-level factors related to their selection in incident OA.
Chronic neuropathic pain is a common symptom in multiple sclerosis (MS). This randomized controlled single-blinded study investigated whether a new protocol involving five days of transcranial direct current stimulation (tDCS) with an interval period would be effective to reduce pain using the visual analog scale (VAS). Other secondary outcomes included the Neuropathic Pain Scale (NPS), Depression Anxiety Stress Score (DASS), Short Form McGill Pain Questionnaire (SFMPQ), and Multiple Sclerosis Quality of Life 54 (MSQOL54).
Previous research has observed that the speed of alpha band oscillations (8-12 Hz range) recorded during resting electroencephalography is slowed in chronic pain patients. While this slowing may reflect pathological changes that occur during the chronification of pain, an alternative explanation is that healthy individuals with slower alpha oscillations are more sensitive to prolonged pain, and by extension, more susceptible to developing chronic pain. To test this hypothesis, we examined the relationship between the pain-free, resting alpha oscillation speed of healthy individuals and their sensitivity to two models of prolonged pain, Phasic Heat Pain and Capsaicin Heat Pain, at two visits separated by 8 weeks on average (n = 61 Visit 1, n = 46 Visit 2). We observed that the speed of an individual's pain-free alpha oscillations was negatively correlated with sensitivity to both models and that this relationship was reliable across short (minutes) and long (weeks) timescales. Furthermore, the speed of pain-free alpha oscillations can successfully identify the most pain sensitive individuals, which we validated on data from a separate, independent study. These results suggest that alpha oscillation speed is a reliable biomarker of prolonged pain sensitivity with potential for prospectively identifying pain sensitivity in the clinic.
The examination of pain beliefs for chronic pain assessment and treatment has been a growing area of interest. A variety of questionnaires have been developed to assess pain beliefs, however, these questionnaires often require high levels of literacy and education. The Pain Concepts Questionnaire (PCQ) was developed with literacy-adaptations to better evaluate pain beliefs in a low socioeconomic (SES) population. This study is an initial exploratory evaluation of the PCQ in a sample of patients with chronic pain and multiple disparities as part of the Learning About My Pain (LAMP) trial, a randomized controlled trial comparing literacy-adapted psychosocial treatments for chronic pain. All data were collected at pre-treatment. Exploratory factor analysis (EFA) was performed to examine the underlying factor structure of the PCQ and cross-sectional correlational analyses examined relationships between pain beliefs with sociodemographic factors and chronic pain-related variables. Results suggested a 2-factor solution with a Biopsychosocial factor and Biomedical factor. Consistent with the literature, correlational analyses highlighted racial and SES disparities in pain beliefs and the importance of beliefs in pain- and cognitive/affective-related functioning. The study emphasizes the importance of pain beliefs in chronic pain management and recommends future research to further examine additional psychometric properties of the PCQ.
Chemotherapy-induced peripheral neuropathy is a serious adverse effect of chemotherapeutic agents such as paclitaxel. JTC-801, a nociceptin/orphanin FQ opioid peptide (NOP) receptor antagonist, has been reported to attenuate neuropathic pain in several pain models. However, the therapeutic significance and function of JTC-801 in chemotherapy-induced peripheral neuropathy remain unclear. In this study, we determined the effect of JTC-801 on neuropathic pain induced by paclitaxel, and we explored the potential mechanism in the dorsal root ganglion (DRG). The behavioral test showed that single or multiple systemic administrations of JTC-801 significantly alleviated mechanical allodynia in paclitaxel-treated rats. Using Western blot analysis and immunohistochemistry, we found that paclitaxel increased the expression of phosphatidylinositol 3-kinase (PI3K) and phospho-Akt (p-Akt) in the DRG. Double immunofluorescence staining indicated that p-Akt was expressed in neurons in the DRG. Multiple injections of JTC-801 significantly inhibited the activation of Akt and decreased the expression of inflammatory cytokines. The data suggest that JTC-801 alleviates mechanical allodynia associated with paclitaxel-induced neuropathic pain via the PI3K/Akt pathway.
To review and assess the methodological quality of randomised controlled trials that test physical therapy interventions for low back pain.
Spinal cord injury (SCI) causes neurodegeneration, impairs locomotor function, and impacts the quality of life particularly in those individuals that develop neuropathic pain. Whether the time course of neurodegeneration, locomotor impairment, or neuropathic pain varies with sex, however, remains understudied. Therefore, the objective of this study in male and female C57BL/6 mice was to evaluate the following outcomes for six weeks after a 75-kdyn thoracic contusion SCI: locomotor function using the Basso Mouse Scale (BMS); spinal cord tissue sparing and rostral-caudal lesion length; and mechanical allodynia and heat hyperalgesia using hindpaw application of Von Frey filaments or radiant heat stimuli, respectively. Although motor function was largely similar between sexes, all of the males, but only half of the females, recovered plantar stepping. Rostral-caudal lesion length was shorter in females than in males. All animals, regardless of sex, developed mechanical allodynia and heat hyperalgesia after SCI; there were no differences in pain outcomes between sexes. We conclude that contusion SCI yields subtle sex differences in mice depending on the outcome measure but no significant differences in behavioral signs of neuropathic pain.