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Heteromers between mu opioid receptor (MOPr) and delta opioid receptor (DOPr) (i.e., MOPr-DOPr heteromer) have been found to be expressed in different brain regions, in the spinal cord, and in dorsal root ganglia. Recent studies on this heteromer reveal its important pathophysiological function in pain regulation including neuropathic pain; this suggests a role as a novel therapeutic target in chronic pain management. In addition, receptor transporter protein 4 (RTP4) has been shown to be involved in the intracellular maturation of the MOPr-DOPr heteromers. RTP4 appears to have unique distribution being highly expressed in sensory neurons and also macrophages; the latter are effector cells of the innate immune system that phagocytose foreign substances and secrete both pro-inflammatory and antimicrobial mediators; this suggests a possible contribution of RTP4 to neuronal immune-related pathological conditions such as neuropathic pain. Although RTP4 could be considered as an important therapeutic target in the management of pain via MOPr-DOPr heteromer, a few reports have supported this. This review will summarize the possible role or functions of the MOPr-DOPr heteromer and its regulatory molecule RTP4 in pain modulation at sensory neurons.
Learn More >Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.
Learn More >Disruption of blood-brain barrier integrity and dramatic failure of brain ion homeostasis including fluctuations of pH occurs during cortical spreading depression (CSD) events associated with several neurological disorders, including migraine with aura, traumatic brain injury and stroke. NHE1 is the primary regulator of pH in the central nervous system. The goal of the current study was to investigate the role of sodium-hydrogen exchanger type 1 (NHE1) in blood brain barrier (BBB) integrity during CSD events and the contributions of this antiporter on xenobiotic uptake. Using immortalized cell lines, pharmacologic inhibition and genetic knockdown of NHE1 mitigated the paracellular uptake of radiolabeled sucrose implicating functional NHE1 in BBB maintenance. In contrast, loss of functional NHE1 in endothelial cells facilitated uptake of the anti-migraine therapeutic, sumatriptan. In female rats, cortical KCl but not aCSF selectively reduced total expression of NHE1 in cortex and PAG but increased expression in trigeminal ganglia; no changes were seen in trigeminal nucleus caudalis. Thus, in vitro observations may have a significance in vivo to increase brain sumatriptan levels. Pharmacological inhibition of NHE1 prior to cortical manipulations enhanced the efficacy of sumatriptan at early time-points but induced facial sensitivity alone. Overall, our results suggest that dysregulation of NHE1 contributes to breaches in BBB integrity, drug penetrance, and the behavioral sensitivity to the antimigraine agent, sumatriptan.
Learn More >Cannabidiol (CBD), the major non-psychoactive constituent of L., has gained traction as a potential treatment for intractable chronic pain in many conditions. Clinical evidence suggests that CBD provides therapeutic benefit in certain forms of epilepsy and imparts analgesia in certain conditions, and improves quality of life. CBD continues to be Schedule I or V on the list of controlled substances of the Drug Enforcement Agency of the United States. However, preparations labeled CBD are available publicly in stores and on the streets. However, use of CBD does not always resolve pain. CBD purchased freely entails the risk of adulteration by potentially hazardous chemicals. As well, CBD use by pregnant women is rising and poses a major health-hazard for future generations. In this mini-review, we present balanced and unbiased pre-clinical and clinical findings for the beneficial effects of CBD treatment on chronic pain and its deleterious effects on prenatal development.
Learn More >In the United States (US), long-term opioid therapy has been commonly prescribed for chronic pain. Since recognition of the opioid overdose epidemic, clinical practice guidelines have recommended tapering long-term opioids to reduced doses or discontinuation. The Effects of Prescription Opioid Changes for veterans (EPOCH) study is a national population-based prospective observational study of US Veterans Health Administration primary care patients designed to assess effects of evolving opioid prescribing practice on patients treated with long-term opioids for chronic pain. A stratified random sampling design was used to identify a survey sample from the target population of patients treated with opioid analgesics for ≥ 6 months. Demographic, diagnostic, visit, and pharmacy dispensing data were extracted from existing datasets. A 2016 mixed-mode mail and telephone survey collected patient-reported data, including the main patient-reported outcomes of pain-related function (Brief Pain Inventory interference; BPI-I scores 0-10, higher scores = worse) and health-related quality of life. Data on survey participants and non-participants were analyzed to assess potential nonresponse bias. Weights were used to account for design. Linear regression models were used to assess cross-sectional associations of opioid treatment with patient-reported measures. Of 14,160 patients contacted, 9253 (65.4%) completed the survey. Participants were older than non-participants (63.9 ± 10.6 vs. 59.6 ± 13.0 years). The mean number of bothersome pain locations was 6.8 (SE 0.04). Effectiveness of pain treatment and quality of pain care were rated fair or poor by 56.1% and 45.3%, respectively. The opioid daily dosage range was 1.6 to 1038.2 mg, with mean = 50.6 mg (SE 1.1) and median = 30.9 mg (IQR 40.7). Among the 73.2% of patients who did not receive long-acting opioids, the mean daily dosage was 30.4 mg (SE 0.6) and mean BPI-I was 6.4 (SE 00.4). Among patients who received long-acting opioids, the mean daily dosage was 106.2 mg (SE 2.8) and mean BPI-I was 6.8 (SE 0.07). Higher daily dosage was associated with worse pain-related function and quality of life among patients without long-acting opioids, but not among patients with long-acting opioids. Future analyses will use follow-up data to examine effects of opioid dose reduction and discontinuation on patient outcomes.
Learn More >CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes.
Learn More >Evaluation of cannabinoid receptor agonists in a preclinical model of medication overuse headache.
Learn More >Systemic treatments for severe childhood atopic dermatitis have limited evidence and/or are unlicensed. Despite the efficacy of anti-IgE medication (omalizumab) in the treatment of atopy, no large randomized studies in childhood atopic dermatitis have been published.
Learn More >Ceruletide (CRL) is a decapeptide, originating from the skin of a tropical frog, and is many times more potent that cholecystokinin (CCK) in a number of assays. The compound was first isolated and characterized around 50 years ago, and its analgesic properties were subsequently identified. Since the 1980s it has been available in the clinic as a parenteral solution and is used as a diagnostic tool to characterize pancreas and gall bladder malfunctions. Its analgesic properties were evaluated in a number of indications: cancer pain, burns, colic pains and migraine. Preclinically, CRL reduces pain in low microgram dose range and promotes clear and long-lasting analgesic activity in nanograms when applied centrally. CCK is amongst the most widely expressed neuropeptides in the brain. CCK-induced analgesic effects in response to persistent and inflammatory pain have recently been associated with CCK2 receptor signaling. CRL, a potent CCK agonist, might be worthwhile to rediscover as a putative analgesic drug and could represent a potential analgesic intrathecal strategy to patients with cancer-related pain.
Learn More >Paclitaxel is a representative anticancer drug that induces chemotherapy-induced peripheral neuropathy (CIPN), a common side effect that limits many anticancer chemotherapies. Although PINK1, a key mediator of mitochondrial quality control, has been shown to protect neuronal cells from various toxic treatments, the role of PINK1 in CIPN has not been investigated. Here, we examined the effect of PINK1 expression on CIPN using a recently established paclitaxel-induced peripheral neuropathy model in Drosophila larvae. We found that the class IV dendritic arborization (C4da) sensory neuron-specific expression of PINK1 significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype. In contrast, knockdown of PINK1 resulted in an increase in thermal hypersensitivity, suggesting a critical role for PINK1 in sensory neuron-mediated thermal nociceptive sensitivity. Interestingly, analysis of the C4da neuron morphology suggests that PINK1 expression alleviates paclitaxel-induced thermal hypersensitivity by means other than preventing alterations in sensory dendrites in C4da neurons. We found that paclitaxel induces mitochondrial dysfunction in C4da neurons and that PINK1 expression suppressed the paclitaxel-induced increase in mitophagy in C4da neurons. These results suggest that PINK1 mitigates paclitaxel-induced sensory dendrite alterations and restores mitochondrial homeostasis in C4da neurons and that improvement in mitochondrial quality control could be a promising strategy for the treatment of CIPN.
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