Accepted

Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) that have been identified at approximately 0.7 and 0.5 million loci in the human genome, respectively, are highly multi-allelic variations rather than single-nucleotide polymorphisms. The number of repeats of more than a few thousand STRs was associated with the expression of nearby genes, indicating that STRs are influential genetic variations in human traits. Analgesics act on the central nervous system via their intrinsic receptors to produce analgesic effects. In the present study, we focused on STRs and VNTRs in the , , , and genes and analyzed two peripheral pain sensation-related traits and seven analgesia-related traits in postoperative pain management. A total of 192 volunteers who underwent the peripheral pain sensation tests and 139 and 252 patients who underwent open abdominal and orthognathic cosmetic surgeries, respectively, were included in the study. None of the four STRs or VNTRs were associated with peripheral pain sensation. Short tandem repeats in the , , and genes were associated with the frequency of fentanyl use, fentanyl dose, and visual analog scale pain scores 3 h after orthognathic cosmetic surgery (Spearman's rank correlation coefficient = 0.199, = 0.002, = 0.174, = 0.006, and = 0.135, = 0.033, respectively), analgesic dose, including epidural analgesics after open abdominal surgery ( = -0.200, = 0.018), and visual analog scale pain scores 24 h after orthognathic cosmetic surgery ( = 0.143, = 0.023), respectively. The associations between STRs in the gene and the frequency of fentanyl use and fentanyl dose after orthognathic cosmetic surgery were confirmed by Holm's multiple-testing correction. These findings indicate that STRs in the gene influence analgesia in the orofacial region.

Although μ-opioid peptide (MOP) receptor agonists are effective analgesics available in clinical settings, their serious adverse effects put limits on their use. The marked increase in abuse and misuse of prescription opioids for pain relief and opioid overdose mortality in the past decade has seriously impacted society. Therefore, safe analgesics that produce potent analgesic effects without causing MOP receptor-related adverse effects are needed. This review highlights the potential therapeutic targets for the treatment of opioid abuse and pain based on available evidence generated through preclinical studies and clinical trials. To ameliorate the abuse-related effects of opioids, orexin-1 receptor antagonists and mixed nociceptin/MOP partial agonists have shown promising results in translational aspects of animal models. There are several promising non-opioid targets for selectively inhibiting pain-related responses, including nerve growth factor inhibitors, voltage-gated sodium channel inhibitors, and cannabinoid- and nociceptin-related ligands. We have also discussed several emerging and novel targets. The current medications for opioid abuse are opioid receptor-based ligands. Although neurobiological studies in rodents have discovered several non-opioid targets, there is a translational gap between rodents and primates. Given that the neuroanatomical aspects underlying opioid abuse and pain are different between rodents and primates, it is pivotal to investigate the functional profiles of these non-opioid compounds compared to those of clinically used drugs in non-human primate models before initiating clinical trials. More pharmacological studies of the functional efficacy, selectivity, and tolerability of these newly discovered compounds in non-human primates will accelerate the development of effective medications for opioid abuse and pain.

The outbreak of COVID-19 poses a serious threat to global health. Musculoskeletal (MSK) pain is the most frequent symptom in patients with COVID-19 besides fever and cough. There are limited studies addressing MSK symptoms in patients with COVID-19. This review aims to provide an overview of current studies related to MSK pain in patients with COVID-19, summarize the possible mechanisms of myalgia, and describe the current management options. In addition to acute respiratory manifestations, COVID-19 might also affect neurological systems which include skeletal manifestations and muscular injury. A possible mechanism of MSK pain and myalgia in COVID-19 may be related to the distribution of angiotensin-converting enzyme 2 (ACE-2) and the occurrence of cytokine storms. ACE-2 has been shown to be the receptor of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV2). Moreover, studies have shown that inflammatory cytokines could cause myalgia by inducing prostaglandin E2 (PGE2) production. In addition, it was also found that the plasma levels of IL2, IL7, IL10, IL-6, TNFα, and e lymphopenia were higher in patients with COVID-19. In general, the treatment of MSK pain in patients with COVID-19 falls into pharmacological and non-pharmacological interventions. Various treatments of each have its own merits. The role of vaccination is irreplaceable in the efforts to prevent COVID-19 and mitigates its subsequent symptoms.

A major limitation in treatment outcomes for chronic pain is the heterogeneity of the population. Therefore, a personalized approach to the assessment and treatment of children and adolescents with chronic pain conditions is needed. The objective of the study was to subgroup pediatric patients with chronic MSK pain that will be phenotypically different from each other based on their psychosocial profile, somatosensory function, and pain modulation.

Chronic pelvic pain (CPP) affects a significant proportion of women worldwide And has a negative impact on several aspects of these women's lives including mental health, work, relationships and sexual function, among others. This set of factors ultimately reflects negatively on quality Of life. The physiopathology of CPP is complex and remains to be fully clarified; however, recent advances have increased understanding of the mechanisms involved in chronic pain in general, and more specifically, CPP. Nonetheless, even when a detailed clinical history is obtained, meticulous physical examination is performed and imaging resources are appropriately used, the organic cause of the pain may still fail to be identified in a substantial number of women with CPP. Management of CPP may therefore be challenging. This narrative review was aimed at adding to the available literature on the subject, presenting and discussing the principal characteristics of CPP in women. The paper highlights gaps in the literature while providing the most up-to-date evidence associated with the physiopathology and classification of pain, its diagnosis and treatment. In addition, current challenges in the management of women with CPP are discussed.

Knee osteoarthritis (KOA) is a debilitating disease characterized by chronic pain, stiffness, and decreased mobility. Intra-articular injectable therapies show good clinical efficacy in improving symptoms; however, these therapies and their comparators (intra-articular saline) have been associated with a large underlying placebo effect. We aimed to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect in clinical trials in KOA. A targeted literature review was conducted by searching Embase, MEDLINE®, and CENTRAL using predefined study selection criteria. All eligible studies identified were extracted for relevant data, and results were narratively summarized. Forty-three studies were included following screening. Challenges associated with the intra-articular placebo effect included its ability to mask the comparative efficacy of active treatments in trials ( = 7 studies), long-lasting effects (up to 6 months;  = 3), and substantial variation of placebo effect sizes across populations ( = 3). Hypotheses for the mechanism of the placebo effect included aspiration of synovial fluid during administration ( = 6) and dilution of inflammatory mediators ( = 2). Factors affecting the placebo effect size were more invasive routes of administration (e.g., injection oral;  = 4) and patient expectations ( = 2). Proposed solutions included the suggestion for readers to weigh the relevance of clinical trial evidence against the presence of large underlying placebo effects ( = 9), discontinuation of intra-articular saline as an appropriate placebo ( = 5), and inclusion of 'no treatment' or sham injection as a control ( = 4). The intra-articular placebo effect is a well-documented occurrence in KOA clinical trials, and it is suggested that it be accounted for when designing randomized controlled trials. Awareness and understanding of the intra-articular placebo effect in KOA are required for fair interpretation of clinical trial evidence.

GABA receptors containing the 6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. 62 GABA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic 6 GABA receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar 6-containing GABA receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar 6-containing GABA receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via 6-containing GABA receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABA receptor 6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of 6-containing GABA receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating 6-containing GABA receptors. SIGNIFICANCE STATEMENT: 6-Containing GABA receptors are abundantly expressed in cerebellar granule cells, but their pathophysiological roles are widely unknown, and they are thus out of the mainstream of GABA receptor research. Anatomical and electrophysiological evidence indicates that these receptors have a crucial function in neuronal circuits of the cerebellum and the nervous system, and experimental, genetic, post-mortem, and pharmacological studies indicate that selective modulation of these receptors offers therapeutic prospects for a variety of neuropsychiatric disorders and for stress and its consequences.