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Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.
Learn More >Pain is a common symptom in pediatric inflammatory bowel disease (IBD) and is associated with poor health outcomes, yet additional knowledge about the psychosocial correlates of pain is needed to optimize clinical care. The purpose of this study is to systematically review the psychosocial factors associated with pain and pain impact in youth diagnosed with IBD within a developmentally informed framework.
Learn More >We performed a detailed analysis of sensory function in patients with chronic post-surgical neuropathic pain (NP) after breast cancer treatments by quantitative sensory testing (QST) with DFNS (German Research Network on Neuropathic Pain) protocol and bed side examination (BE). The nature of sensory changes in peripheral NP may reflect distinct pathophysiological backgrounds that can guide the treatment choices. NP with sensory gain (i.e., hyperesthesia, hyperalgesia, allodynia) has been shown to respond to Na-channel blockers (e.g., oxcarbazepine).
Learn More >Despite the wide body of research on the properties of the Oswestry Disability Index (ODI), only a few studies have investigated whether ODI scores can be interpreted similarly in both genders. A few previous studies suggested that the ODI may behave differently in different populations, e.g. in different age groups.
Learn More >We investigated cross-sectional associations and whether type 2 diabetes increases the risk of musculoskeletal pain after adjusting for the presence of important comorbidities.
Learn More >Opioids are widely used in clinical practice because of their strong analgesia. However, their use is restricted by such factors as tolerance and opioid-induced hyperalgesia (OIH), so it is critical to find ways to reduce the dosage of opioids to avoid the side effects. In this study, we demonstrated for the first time the regulatory role of A20 in morphine analgesia. By overexpressing and knocking down A20 in the spinal cord of mice, we found that A20 enhanced morphine analgesia rather than tolerance. Then, at the cellular level, different methods were used to confirm that A20 could not only strengthen the inhibition of cAMP induced by opioids drugs, but also affect μ opioid receptor (MOR) and ERK phosphorylation. In addition, we found that A20 interacted with MOR inhibitory protein β-arrestin2, which could be enhanced by MOR agonists. Furthermore, there was evidence that A20 could inhibit β-arrestin2 recruitment. Collectively, our results indicated that A20 in the spinal cord could enhance morphine analgesia and increase MOR function through β-arrestin2. Upregulating A20 expression may be a potential strategy to improve the therapeutic profile of opioids and reduce their side effects.
Learn More >Substance use disorders (SUDs) are frequently accompanied by affective symptoms that promote negative reinforcement mechanisms contributing to SUD maintenance or progression. Despite their widespread use as analgesics, chronic or excessive exposure to alcohol, opioids, and nicotine produces heightened nociceptive sensitivity, termed hyperalgesia. This review focuses on the contributions of neuropeptide (CRF, melanocortin, opioid peptide) and cytokine (IL-1β, TNF-α, chemokine) systems in the development and maintenance of substance-induced hyperalgesia. Few effective therapies exist for either chronic pain or SUD, and the common interaction of these disease states likely complicates their effective treatment. Here we highlight promising new discoveries as well as identify gaps in research that could lead to more effective and even simultaneous treatment of SUDs and co-morbid hyperalgesia symptoms.
Learn More >This systematic review appraises the evidence from human clinical trials comparing post-operative pain scores and opioid consumption in patients receiving intra-articular (IA) ketamine versus other modalities of analgesia after orthopedic joint procedures.
Learn More >Microglia are the resident immune cells in the CNS, which survey the brain parenchyma for pathogens, initiate inflammatory responses, secrete inflammatory mediators, and phagocyte debris. Besides, they play a role in the regulation of brain ion homeostasis and in pruning synaptic contacts and thereby modulating neural networks. More recent work shows that microglia are embedded in brain response related to stress phenomena, the development of major depressive disorders, and pain-associated neural processing. The microglia phenotype varies between activated-toxic-neuroinflammatory to non-activated-protective-tissue remodeling, depending on the challenges and regulatory signals. Increased inflammatory reactions result from brain damage, such as stroke, encephalitis, as well as chronic dysfunctions, including stress and pain. The dimension of damage/toxic stimuli defines the amplitude of inflammation, ranging from an on-off event to low but continuous simmering to uncontrollable. Pain, either acute or chronic, involves inflammasome activation at the point of origin, the different relay stations, and the sensory and processing cortical areas. This short review aimed at identifying a sinister role of the microglia-inflammasome platform for the development and perpetuation of acute and chronic central pain and its association with changes in CNS physiology.
Learn More >With over 30% of current medications targeting this family of proteins, G-protein-coupled receptors (GPCRs) remain invaluable therapeutic targets. However, due to their unique physicochemical properties, their low abundance, and the lack of highly specific antibodies, GPCRs are still challenging to study in vivo. To overcome these limitations, we combined here transgenic mouse models and proteomic analyses in order to resolve the interactome of the δ-opioid receptor (DOPr) in its native in vivo environment. Given its analgesic properties and milder undesired effects than most clinically prescribed opioids, DOPr is a promising alternative therapeutic target for chronic pain management. However, the molecular and cellular mechanisms regulating its signaling and trafficking remain poorly characterized. We thus performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses on brain homogenates of our newly generated knockin mouse expressing a FLAG-tagged version of DOPr and revealed several endogenous DOPr interactors involved in protein folding, trafficking, and signal transduction. The interactions with a few identified partners such as VPS41, ARF6, Rabaptin-5, and Rab10 were validated. We report an approach to characterize in vivo interacting proteins of GPCRs, the largest family of membrane receptors with crucial implications in virtually all physiological systems.
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