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Cannabinoid CB receptor (CB) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB, however the involvement of CB from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB agonist JWH133 in wild-type and knockout mice lacking CB in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB knockouts and was increased in mice defective in neuronal CB knockouts suggestive of increased spontaneous pain. Interestingly, CB-positive lymphocytes infiltrated the injured nerve and possible CBtransfer from immune cells to neurons was found. Lymphocyte CBdepletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CBthat protects against spontaneous and evoked neuropathic pain.
Learn More >The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2). We created a transgenic mouse that lacks MORs in vGluT2-expressing neurons (MORflox-vGluT2cre) to demonstrate that MORs on the vGluT2 neurons themselves mediate this synaptic inhibition. We then explored the role of MORs in vGluT2-expressing neurons in opioid-related behaviors. In tests of conditioned place preference, MORflox-vGluT2cre mice did not acquire place preference for a low dose of the opioid, oxycodone, but displayed conditioned place aversion at a higher dose, whereas control mice displayed preference for both doses. In an oral consumption assessment, these mice consumed less oxycodone and had reduced preference for oxycodone compared with controls. MORflox-vGluT2cre mice also failed to show oxycodone-induced locomotor stimulation. These mice displayed baseline withdrawal-like responses following the development of oxycodone dependence that were not seen in littermate controls. In addition, withdrawal-like responses in these mice did not increase following treatment with the opioid antagonist, naloxone. However, other MOR-mediated behaviors were unaffected, including oxycodone-induced analgesia. These data reveal that MOR-mediated regulation of glutamate transmission is a critical component of opioid reward.
Learn More >Fibromyalgia (FM) is one of the most common musculoskeletal pain conditions. Although the aetiology of FM is still unknown, mitochondrial dysfunction and the overproduction of reactive oxygen intermediates (ROI) are common characteristics in its pathogenesis. The reserpine experimental model can induce FM-related symptoms in rodents by depleting biogenic amines. However, it is unclear whether reserpine causes other pathophysiologic characteristics of FM. So far, no one has investigated the relevance of mitochondrial dysfunction in the reserpine-induced experimental FM model using protection- and insult-based mitochondrial modulators. Reserpine (1 mg/kg) was subcutaneously injected once daily for three consecutive days in male Swiss mice. We carried out analyses of reserpine-induced FM-related symptoms, and their modulation by using mitochondrial insult on ATP synthesis (oligomycin; 1 mg/kg, intraperitoneally) or mitochondrial protection (coenzyme Q10; 150 mg/kg/5 days, orally). We also evaluated the effect of reserpine on mitochondrial function using high-resolution respirometry and oxidative status. Reserpine caused nociception, loss in muscle strength, and anxiety- and depressive-like behaviours in mice that were consistent with clinical symptoms of FM, without inducing body weight and temperature alterations or motor impairment. Reserpine-induced FM-related symptoms were increased by oligomycin and reduced by coenzyme Q10 treatment. Reserpine caused mitochondrial dysfunction by negatively modulating the electron transport system and mitochondrial respiration (ATP synthesis) mainly in oxidative muscles and the spinal cord. These results support the role of mitochondria in mediating oxidative stress and FM symptoms in this model. In this way, reserpine-inducing mitochondrial dysfunction and increased production of ROI contribute to the development and maintenance of nociceptive, fatigue, and depressive-like behaviours.
Learn More >The lack of biomarkers indicating involved nociceptive and/or pain mechanisms makes diagnostic procedures problematic. Clinical pain research has begun to use proteomics.
Learn More >Since the end of 2019, the whole world has been struggling with the pandemic of the new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Available evidence suggests that pain is a common symptom during Coronavirus Disease 2019 (COVID-19). According to the World Health Organization, many patients suffer from muscle pain (myalgia) and/or joint pain (arthralgia), sore throat and headache. The exact mechanisms of headache and myalgia during viral infection are still unknown. Moreover, many patients with respiratory failure get admitted to the intensive care unit (ICU) for ventilatory support. Pain in ICU patients can be associated with viral disease itself (myalgia, arthralgia, peripheral neuropathies), may be caused by continuous pain and discomfort associated with ICU treatment, intermittent procedural pain and chronic pain present before admission to the ICU. Undertreatment of pain, especially when sedation and neuromuscular blocking agents are used, prone positioning during mechanical ventilation or extracorporeal membrane oxygenation (ECMO) may trigger delirium and cause peripheral neuropathies. This narrative review summarizes current knowledge regarding challenges associated with pain assessment and management in COVID-19 patients. A structured prospective evaluation should be undertaken to analyze the probability, severity, sources and adequate treatment of pain in patients with COVID-19 infection.
Learn More >The salience network is responsive during a range of conditions requiring immediate behavioral responses, including pain processing. Resting-state functional connectivity of the salience network to the sensorimotor cortex is altered in chronic pain. However, little is understood about their fundamental communication in the absence of pain. In this study, we mapped salience network resting-state functional connectivity across sensorimotor cortex in healthy individuals. Using electromyography and task-based functional magnetic resonance imaging (fMRI), we first localized distinct regions-of-interest across sensorimotor cortex in medial (gluteal), intermediate (shoulder), and lateral (hand) areas. We then used resting-state fMRI for two cohorts (primary and replication) of healthy individuals from public repositories to map salience network resting-state functional connectivity across sensorimotor cortex. Both the primary and replication cohorts exhibited significant heterogeneity in salience network resting-state functional connectivity across the sensorimotor regions-of-interest. Using a cortical flatmap to visualize the entire sensorimotor surface, we observed similar heterogeneity in both cohorts. In general, the somatotopic representation of proximal body regions (trunk/face) had higher salience network resting-state functional connectivity compared to distal body regions (upper/lower limbs). We conclude that sensorimotor cortex is spatially heterogeneous in its interaction with the salience network in healthy individuals.
Learn More >At the conception of this study (January 2019), a literature search by the authors found no evidence-based or consensus perioperative guidelines for patients consuming cannabis products, or for those patients in whom a cannabinoid medication could be considered for perioperative treatment. Currently, there is a large global population that consumes cannabis. The availability of cannabis has also increased this decade with greater legal access to cannabis products in some countries such as USA, Canada, Uruguay, Israel, Australia and Germany. There are recognised possible therapeutic benefits for the use of cannabis in patients with chronic pain, chronic neuropathic pain and chemotherapy-induced nausea and vomiting. There are also potential side effects from cannabis use such as psychosis, cannabis hyperemesis syndrome, misuse disorder and cannabis withdrawal syndrome. There is evidence that cannabis may also affect factors in the perioperative period such as monitoring, quality of analgesia, sleep and opioid consumption. Given the large population of persons using cannabis, the heterogeneity of cannabis products and the paucity (and heterogeneity) of perioperative literature surrounding it, perioperative guidelines for cannabis consuming patients are both lacking and necessary. In this paper, we present the design for a modified Delphi technique that has been started with the intent of deriving cannabis perioperative guidelines from the available medical literature and the consensus of multidisciplinary experts.
Learn More >Chronic mechanical low back pain (cLBP) is a leading cause of disability and a major socio-economic burden internationally. The lifetime prevalence of non-specific LBP is approximately 84%, with the prevalence of cLBP at about 23%. Clinically available analgesic/adjuvant medications often provide inadequate pain relief in patients experiencing cLBP. Hence, the urgency for discovery of effective and better tolerated medications. Fourteen days after the induction of 5 shallow annular punctures (5X) in the lumbar intervertebral discs at L4/L5 and L5/L6 in male Sprague-Dawley rats, mechanical hyperalgesia was fully developed in the lumbar axial deep tissues at L4/L5 (primary) and L1 (secondary). Importantly, mechanical allodynia in the hindpaws was absent. From day 28, we assessed the face validity of our mild to moderate LBP-5X rat model using four clinically available analgesic/adjuvant drugs, namely gabapentin, morphine, meloxicam and amitriptyline relative to vehicle. Additionally, the anti-hyperalgesic effects of J-2156, a highly selective small molecule somatostatin type 4 receptor agonist was assessed. Single i.p. bolus doses of gabapentin and meloxicam at the highest doses tested (100 and 30 mg/kg respectively) alleviated secondary hyperalgesia (L1) but not primary hyperalgesia (L4/5). Morphine at 1 mg/kg alleviated both primary and secondary hyperalgesia in these tissues, whereas amitriptyline at the doses tested, lacked efficacy. These findings attest to the face validity of our model. J-2156 at 10 and 30 mg/kg alleviated secondary hyperalgesia in the lumbar axial deep tissues at L1 with a non-significant trend for relief of primary hyperalgesia in the corresponding tissues at L4/L5 in these animals.
Learn More >Opioids are extensively used in patients with cancer pain; despite their efficacy, several patients can experience ineffective analgesia and/or side effects. Pharmacogenetics is a new approach to drug prescription based on the "personalized-medicine" concept, i.e., the ability of tailoring treatments to each individual's genetic/genomic profile. Pharmacogenetics aims to identify specific genetic variants that influence pharmacokinetics and pharmacodynamics of drugs, better determining their effectiveness/safety profile. Opioid response is a complex scenario, but some gene variants have shown a correlation with pain sensitivity, as well as with opioid metabolism and clinical efficacy/adverse events. Although questions remain unanswered, some of these gene variants may already be used to identify specific patients' phenotypes that are more prone to experience better clinical response (i.e., better analgesia and/or less adverse events). Once adopted, this approach to opioid prescription may improve a patient's outcome. This review summarizes the available data on genetic variants and opioid response: we will focus on basic pharmacogenetic and its impact in the clinical scenario discussing how they may lead to more appropriate opioid prescription in cancer patients.
Learn More >TRPA1 is a non-selective cation channel predominantly expressed in sensory neurons, and functions as an irritant sensor for a plethora of noxious external stimuli and endogenous ligands associated with cell damage. Due to its involvement in pain, itch, and respiratory syndromes, TRPA1 has been pursued as a promising drug target.
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