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Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.
Learn More >Crosstalk between Sirtuins and Nrf2: SIRT1 activators as emerging treatment for diabetic neuropathy.
About 50% of the diabetic patients worldwide suffer from Diabetic peripheral neuropathy (DPN) which is characterized by chronic pain and loss of sensation, frequent foot ulcerations, and risk for amputation. Numerous factors like hyperglycemia, oxidative stress (OS), impaired glucose signaling, inflammatory responses, neuronal cell death are known to be the various mechanisms underlying DACD and DPN. Development of tolerance, insufficient and inadequate relief and potential toxicity of classical antinociceptives still remains a challenge in the clinical setting. Therefore, there is an emerging need for novel treatments which are both without any potential side effects as well as which focus more on the pathophysiological mechanisms underlying the disease. Also, sirtuins are known to deacetylate Nrf2 and contribute to its action of reducing ROS by generation of anti-oxidant enzymes. Therefore, targeting sirtuins could be a favourable therapeutic strategy to treat diabetic neuropathy by reducing ROS and thereby alleviating OS in DPN. In the present review, we outline the potential use of SIRT1 activators as therapeutic alternatives in treating DPN. We have tried to highlight how sirtuins are interlinked with Nrf2 and NF-κB and put forth how SIRT activators could serve as potential therapy for DPN.
Learn More >Sickle cell disease (SCD) is the most common inherited disease. Pain is a key morbidity of SCD and opioids are the main treatment but their side effects emphasize the need for new analgesic approaches. Humanized transgenic mouse models have been instructive in understanding the pathobiology of SCD and mechanisms of pain. Homozygous (HbSS) Berkley mice express >99% human sickle hemoglobin and several features of clinical SCD including hyperalgesia. Previously, we reported that the endocannabinoid 2-arachidonoylglycerol (2-AG) is a precursor of the pro-nociceptive mediator prostaglandin E2-glyceryl ester (PGE2-G) which contributes to hyperalgesia in SCD. We now demonstrate the causal role of 2-AG in hyperalgesia in sickle mice. Hyperalgesia in HbSS mice correlated with elevated levels of 2-AG in plasma, its synthesizing enzyme diacylglycerol lipase β (DAGLβ) in blood cells, and with elevated levels of PGE2 and PGE2-G, pro-nociceptive derivatives of 2-AG. A single intravenous injection of 2-AG produced hyperalgesia in non-hyperalgesic HbSS mice, but not in control (HbAA) mice expressing normal human HbA. JZL184, an inhibitor of 2-AG hydrolysis also produced hyperalgesia in non-hyperalgesic HbSS or hemizygous (HbAS) mice, but did not influence hyperalgesia in hyperalgesic HbSS mice. Systemic and intraplantar administration of KT109, an inhibitor of DAGLβ, decreased mechanical and heat hyperalgesia in HbSS mice. The decrease in hyperalgesia was accompanied by reductions in 2-AG, PGE2 and PGE2-G in the blood. These results indicate that maintaining the physiological level of 2-AG in the blood by targeting DAGLβ may be a novel and effective approach to treat pain in SCD.
Learn More >The clinical use of calcitonin gene-related peptide receptor (CGRP-R) antagonists and monoclonal antibodies against CGRP and CGRP-R has offered new treatment possibilities for migraine patients. CGRP activates both the CGRP-R and structurally related amylin 1 receptor (AMY-R). The relative effect of erenumab and the small-molecule CGRP-R antagonist, rimegepant, towards the CGRP-R and AMY-R needs to be further characterized.
Learn More >Activation of microglia in the spinal cord dorsal horn following peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that following peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.
Learn More >Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past two decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (e.g., cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. Perspective: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.
Learn More >Emotional profile is involved in the experience of chronic pain related to endometriosis. Following the Örebro Model of Behavioral Emotion Regulation of Pain, the aim of this study was to understand the processes involved in the psychological adaptation to pain experienced during menstruations in women either diagnosed or not diagnosed with endometriosis.
Learn More >Feeding behaviors are closely associated with chronic pain in adult rodents. Our recent study revealed that 2 hours refeeding after 24 hours fasting (i.e., refeeding) attenuates pain behavior under chronic inflammatory pain conditions. However, while brain circuits mediating fasting-induced analgesia have been identified, the underlying mechanism of refeeding-induced analgesia is still elusive. Herein, we demonstrate that the neural activities in the nucleus accumbens shell (NAcS) and anterior insular cortex (aIC) were increased in a modified Complete Freund's Adjuvant (Lutz, #26)-induced chronic inflammatory pain condition, which was reversed by refeeding. We also found that refeeding reduced the enhanced excitability of aIC-NAcS projecting neurons in this CFA model. Besides, chemogenetic inhibition of aIC-NAcS neural circuit suppressed chronic pain behavior while activation of this circuit reversed refeeding-induced analgesia. Thus, the present study suggests that aIC-NAcS neural circuit mediates refeeding-induced analgesia, thereby serving as a potential therapeutic target to manage chronic pain.
Learn More >Fibromyalgia syndrome (FMS) is a chronic pain condition accompanied by affective symptoms and cognitive impairments. This study investigated central nervous correlates of attentional and emotional processing in FMS. Therefore, event-related potentials were recorded in 26 FMS patients and 26 healthy controls during a dot probe task, which required participants to decide which side of the screen an asterisk was displayed on; the asterisk was immediately preceded by a facial expression (anger, pain, happiness, neutral) on the left or right side. Comorbid depression was also assessed. In patients, N170 amplitude was smaller for anger and pain expressions than for happy expressions, and P2 was greater for pain expressions than for happy expressions. N170 and P2 were unaffected by emotional expressions in controls. LPC was smaller overall in patients than controls. Though reaction times were longer overall in patients than controls, no behavioral effects of emotional stimuli arose in these groups. In contrast, FMS patients with comorbid depression showed less attentional interference due to emotional expressions, and less difficulty disengaging from these stimuli than patients without depression. While the observations concerning N170 suggested facilitated encoding of facial features representing negative rather than positive emotions in FMS and more automatized processing of pain expressions, those for P2 indicated increased attentional resource allocation to pain-related information. Reduced LPC reflects nonspecific deficits in sustained attention in FMS, which is in line with the longer reaction times. Behavioral data suggest lower processing depth of emotional information in patients with comorbid depression.
Learn More >Acute respiratory distress syndrome (ARDS), a severe medical condition, is among the major causes of death in critically ill patients. Morphine is used as a therapeutic agent against severe pain. The mechanisms of its reactions over ARDS are not fully understood. The aim of this study was to assess the mechanism of morphine in rats with ARDS.
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