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Adenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A, A, A, and A adenosine receptors (ARs). In recent years, extensive progress has been made to elucidate the role of adenosine in pain regulation. Most of the antinociceptive effects of adenosine are dependent upon AAR activation located at peripheral, spinal, and supraspinal sites. The role of AAR and AAR is more controversial since their activation has both pro- and anti-nociceptive effects. AAR agonists are emerging as promising candidates for neuropathic pain. Although their therapeutic potential has been demonstrated in diverse preclinical studies, no AR ligands have so far reached the market. To date, novel pharmacological approaches such as adenosine regulating agents and allosteric modulators have been proposed to improve efficacy and limit side effects enhancing the effect of endogenous adenosine. This review aims to provide an overview of the therapeutic potential of ligands interacting with ARs and the adenosinergic system for the treatment of acute and chronic pain.
Learn More >Human immunodeficiency virus type-1 (HIV-1) and opiates cause long-term inflammatory insult to the central nervous system (CNS) and worsen disease progression and HIV-1-related neuropathology. The combination of these proinflammatory factors reflects a devastating problem as opioids have high abuse liability and continue to be prescribed for certain patients experiencing HIV-1-related pain.
Learn More >Use of parenteral opioids is a major risk factor for postoperative nausea and vomiting. Conventional opioids bind to µ-opioid receptors (MOR), stimulate both the G-protein signaling (achieving analgesia); and the β-arrestin pathway (associated with opioid-related adverse effects). Oliceridine, a next-generation IV opioid, is a G-protein selective MOR agonist, with limited recruitment of β-arrestin. In two randomized, placebo- and morphine-controlled phase 3 studies of patients with moderate-to-severe acute pain following bunionectomy or abdominoplasty, oliceridine at demand doses of 0.1, 0.35, and 0.5 mg provided rapid and sustained analgesia vs. placebo with favorable gastrointestinal (GI) tolerability. In this exploratory analysis, we utilized a clinical endpoint assessing gastrointestinal tolerability, "complete GI response" defined as the proportion of patients with no vomiting and no use of rescue antiemetic to characterize the GI tolerability profile of oliceridine vs. morphine.
Learn More >The aim of the study was to investigate patient satisfaction amongst academic pain management centers and associated factors.
Learn More >Preclinical studies demonstrate that sleep disruption diminishes morphine analgesia and modulates reward processing. We sought to translate these preclinical findings to humans by examining whether sleep disruption alters morphine's analgesic and hedonic properties. We randomized 100 healthy adults to receive morphine versus placebo after two nights of undisturbed sleep (US) and two nights of forced awakening (FA) sleep disruption. Sleep conditions were counterbalanced, separated by a two-week washout. The morning after both sleep conditions, we tested cold pressor pain tolerance before and 40-min after double-blind injection of .08 mg/kg morphine or placebo. The primary outcome was the analgesia index, calculated as the change in cold pressor hand withdrawal latency (HWL) before and after drug injection. Secondary outcomes were ratings of feeling "high," drug "liking," and negative drug effects. We found a significant sleep condition by drug interaction on the analgesia index (95% CI - 0.57, - 0.001). After US, subjects receiving morphine demonstrated significantly longer HWL compared to placebo (95% CI 0.23, 0.65), but not after FA (95% CI - 0.05, 0.38). Morphine analgesia was diminished threefold under FA, relative to US. After FA, females (95% CI - 0.88, - 0.05), but not males (95% CI - 0.23, 0.72), reported decreased subjective "high" effects compared to US. After FA, females (95% CI 0.05, 0.27), but not males (95% CI - 0.10, 0.11), administered morphine reported increased negative drug effects compared to US. These data demonstrate that sleep disruption attenuates morphine analgesia in humans and suggest that sleep disturbed males may be at greatest risk for problematic opioid use.
Learn More >To examine the effect of sex on clinical response to triptans and to determine whether these differences are related to pharmacokinetics of triptans in men and women, we performed a systematic review and meta-analysis.
Learn More >In 2006, humans with a congenital insensitivity to pain (CIP) were found to lack functional Na 1.7 channels. In the 15 years since there has been a rush to develop selective Na 1.7 inhibitors with the goal of producing broadly effective analgesics without the problems of addiction and tolerance associated with opioids. Pharmacologically, this mission has been highly successful, leading to a number of highly potent and selective inhibitors of Na 1.7.However,there are very few examples where these inhibitors have yielded effective analgesia in preclinical pain models or human clinical trials. In this review we summarisethe role of Na 1.7 in nociception, its history as a therapeutic target, and the quest to develop potent inhibitors of this channel. Finally, we discuss possible reasons why the pain-free state seen in humans with CIP has been so elusive to recapitulate pharmacologically.
Learn More >Introduction Cluster headache [CH] is a severely disabling trigeminal autonomic cephalalgia [TAC]. Approximately 1 in 1,000 adults are affected by CH. Calcitonin gene related peptide [CGRP] is an important mediator in the pathophysiology of CH. Galcanezumab is a monoclonal antibody with an affinity for the CGRP peptide, FDA approved for prevention of episodic CH. Areas covered Search words queried were 'cluster headache', 'cluster headache and CGRP', 'cluster headache and galcanezumab'. Over 99 articles in Pubmed and prescribing information for galcanezumab was reviewed. Some of the data pertaining to CH trials with fremanezumab were reviewed using clinical trials.org. Expert opinion Galcanezumab has shown benefit in decreasing weekly frequency of CH attacks across week 1 through week 3 in patients with CH; 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (95% confidence interval, 0.2 to 6.7; P = 0.04). It has a favorable risk benefit ratio. The prevention of CH with CGRP inhibition represents a novel advance for a condition with a significant unmet need. The negative trial results of galcanezumab for chronic cluster headache [CCH] may be due to the refractory nature and sheds light on the critical need to investigate the underlying biology and therapeutic options.
Learn More >Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become 'unsilenced' by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.
Learn More >A small number of studies have supported the efficacy of open-label placebos (OLPs) in reducing pain. However, research comparing the effectiveness of OLPs with deceptive placebos (DPs) is limited, and the relative impact on pain tolerance versus intensity are not yet understood. This study therefore, examined the effectiveness of a nasal placebo administered openly and deceptively on pain intensity and tolerance during a cold pressor test (CPT).
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