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The anterior cingulate cortex (ACC) is activated by noxious stimuli and is involved in the affective component of pain processing; but its role in the sensory component of pain remains largely unknown. Studies have verified that Chemokine (C-X-C motif) receptor 3 (CXCR3) is involved in nociceptive sensitization in the spinal cord after peripheral nerve injury; however, the expression of CXCR3 in the ACC and its role in neuropathic pain has not been reported. Here, we showed that CXCR3 co-localized with neurons in the ACC and the upregulation of CXCR3 corresponded with hypersensitive behaviors after a chronic constriction injury of the sciatic nerve. Pharmacological blockade of CXCR3 using local injection of its inhibitor, AMG487, into the ACC significantly attenuated hyperalgesia induced by chronic constriction injury and suppressed the phosphorylation of extracellular signal-regulated kinase (ERK). Collectively, these results suggest that CXCR3 in the ACC is involved in hyperalgesia induced by peripheral nerve injury and ERK may be a downstream target.
Learn More >This prospective study characterized corneal nerve pathway function in individuals with dry eye symptoms. In total, 34% of individuals had a corneal sensitivity outside the 10-90% range or persistent pain after placement of topical anesthesia.
Learn More >Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has an antalgic effect on acute experimental pain in healthy volunteers. Many published studies have used online stimulation (i.e., tDCS performed during painful stimulation). On the other hand, daily tDCS sessions have been proposed as a therapy for chronic pain (offline tDCS). In such cases, the therapeutic potential depends on the possible aftereffects of each tDCS session. We set out to investigate whether a single tDCS session before application of a classical experimental pain paradigm (the Cold Pressor Test, CPT) would be capable of modulating physiological measures of anxiety as well as pain perception. tDCS was applied to 30 healthy volunteers, 18 to 28 years old (mean 18.5), with the anode positioned over either the left M1 or the left dorsolateral prefrontal cortex (l-DLPFC), which has been linked to the affective aspects of experienced pain, including anxiety. All volunteers underwent the CPT procedure before and after a tDCS session. Real 2 mA tDCS sessions for 20 minutes were compared to sham stimulations. No significant difference was found for any variable after real tDCS sessions when compared to the sham simulations. This result suggests that effective offline tDCS for chronic pain might have different mechanisms of action. Cumulative effects, functional targeting and the unintended simultaneous stimulation of both M1 and the l-DLPFC are likely responsible for the therapeutic effects of tDCS sessions in the clinical setting.
Learn More >Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor STAT3 and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.
Learn More >Thousands of individuals die each year from opioid-related overdoses. While naloxone (Narcan®) is currently the most widely employed treatment to reverse opioid toxicity, high or repeated doses of this antidote often lead to precipitated opioid withdrawal (POW). We hypothesized that a slow linear release of naloxone from a nanoparticle would induce fewer POW symptoms compared to high-dose free naloxone. First, we measured the acute impact of covalent naloxone nanoparticles (Nal-cNPs) on morphine-induced antinociception in the hotplate test. We found that Nal-cNP treatment blocked the antinociceptive effect of morphine within 15 min of administration. Next, we tested the impact of Nal-cNPs on POW symptoms in male morphine-dependent mice. To induce morphine dependence, mice were treated with 5 mg/kg morphine (or saline) twice-daily for six consecutive days. On day 7 mice received 5 mg/kg morphine (or saline) injections 2 hr prior to receiving treatment of either unmodified free naloxone, a high or low dose of Nal-cNP, empty nanoparticle (cNP-empty), or saline. Behavior was analyzed for 0-6 hr followed by 24 and 48 hr time points after treatment. As expected, free naloxone induced a significant increase in POW behavior in morphine-dependent mice compared to saline-treated mice upon free naloxone administration. In comparison, reduced POW behavior was observed with both doses of Nal-cNP. Side effects of Nal-cNP on locomotion and fecal boli production were measured and no significant side-effects were observed. Overall, our data show that sustained release of naloxone from a covalent nanoparticle does not induce severe POW symptoms in morphine-dependent mice.
Learn More >The human immunodeficiency virus (HIV) remains a major burden to the health care system and neuropathic pain is the most common neurological complication of HIV infection. Since current treatment strategies often lack satisfying pain relief, cannabinoids are discussed as a new option. We investigated cannabidivarin as treatment for HIV-associated neuropathic pain. We conducted a randomized, double-blind, placebo-controlled cross-over study. Patients underwent two successive treatment phases (4 weeks each) and were treated with cannabidivarin (400mg/d) or placebo in a randomized order. A 3-week wash-out phase was designed to eliminate potential carry-over effects. Patients were followed up for 3 weeks after the end of the second treatment phase. The primary endpoint was pain intensity on an 11-point numeric rating scale, recorded in a diary. Secondary endpoints were additional pain medication, pain characteristics and quality of life. We included 32 patients. The mean pain intensity under cannabidivarin was 0.62 points higher compared to placebo (p=0.16; 95% CI -0.27 to 1.51). Cannabidivarin did not influence the amount of additional pain medication, pain characteristics or quality of life. The incidence of adverse events was similar during both treatments. No suspected unexpected adverse reactions occurred during either treatment. Cannabidivarin was safe but failed to reduce neuropathic pain in HIV-patients. This may be explained by a lack of cannabinoid receptor activation, as indicated by preclinical experiments. Although a larger patient number might be desirable, we would not expect a change in the conclusions since the present differences are far from statistical significance. Therefore, we would currently not consider CBDV as a clinically meaningful treatment option for neuropathic pain.
Learn More >To identify risk factors for pain and functional deterioration in people with knee and hip osteoarthritis (OA) to form the basis of a future 'stratification tool' for OA development or progression.
Learn More >Given the ubiquitous nature of opioids in the treatment of pain, it is an interesting paradox that this class of medications also represents one of the least understood components of clinical pain medicine. For many years, there has been intense interest in the mechanisms of opioid activity, but this has not resulted in a corresponding increase in convincing clinical data. This review focuses primarily on the evidence surrounding the long-term use of opioids in chronic pain, but discussions of this research are often conflated with the very different data governing acute and cancer-related pain, where evidence of efficacy is clearer. It is therefore important to clarify the evidence-based indications for opioid therapy. There remains very little evidence that opioids improve function or quality of life beyond 3 months in people with chronic pain conditions. In all three patient populations, the development of tolerance, dependence, hyperalgesia and withdrawal are key phenomena that affect the patient experience, and in particular the decision to remain on opioids in the long term. This is a common thread that connects the opioid literature in all of these spheres, and justifies the burgeoning interest in these phenomena in the basic science literature. There is an urgent need to address these negative consequences of opioid use, in order to maximize the therapeutic benefit that opioids can offer.
Learn More >Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.
Learn More >Knee osteoarthritis (OA) is a global problem that causes significant pain and physical dysfunction, substantially impacting on quality of life and imposing enormous cost to the healthcare system. Exercise is pivotal to OA management, yet uptake by people with knee OA is inadequate. Limited access to appropriately skilled health professionals, such as physiotherapists, for prescription of an exercise program and support with exercise is a major barrier to optimal care. Internet-enabled video consultations permit widespread reach. However, services offering video consultations with physiotherapists for musculoskeletal conditions are scant in Australia where there is typically no Government or private health insurer funding for such services. The paucity of robust evidence demonstrating video consultations with physiotherapists are clinically effective, safe and cost-effective for knee OA is hampering implementation of, and willingness of healthcare policymakers to pay for, these services.
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