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The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure-activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2',6'-dimethyl-L-Tyr) moiety of [Dmt]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand-MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.
Learn More >Functional interactions between the mu opioid receptor (MOR) and the metabotropic glutamate receptor 5 (mGluR5) in pain and analgesia have been well established. MMG22 is a bivalent ligand containing MOR agonist (oxymorphamine) and mGluR5 antagonist (MPEP) pharmacophores tethered by a 22-atom linker. MMG22 has been shown to produce potent analgesia in several models of chronic inflammatory and neuropathic pain. This study assessed the efficacy of systemic administration of MMG22 at reducing pain behavior in the spared nerve injury (SNI) model of neuropathic pain in mice, as well as its side effect profile and abuse potential. MMG22 reduced mechanical hyperalgesia and spontaneous ongoing pain after SNI, with greater potency early (10 days) as compared to late (30 days) after injury. Systemic administration of MMG22 did not induce place preference in naïve animals, suggesting absence of abuse liability when compared to traditional opioids. MMG22 also lacked the central locomotor, respiratory, and anxiolytic side effects of its monomeric pharmacophores. Evaluation of mRNA expression showed the transcripts for both receptors were co-localized in cells in the dorsal horn of the lumbar spinal cord and dorsal root ganglia. Thus, MMG22 reduces hyperalgesia after injury in the SNI model of neuropathic pain without the typical centrally mediated side effects associated with traditional opioids.
Learn More >Intravenous lidocaine infusions have been shown to be effective for cancer related pain, but access is restricted to acute care settings. If able to be shown to be safe and effective, the subcutaneous route could expand access to residential hospices or patients' homes. This randomized, double-blind, placebo controlled, 2 × 2 crossover trial evaluated the effectiveness, safety, toxicity, and impact on quality of life of a limited duration subcutaneous lidocaine infusion (SCLI) for chronic cancer pain. Patients with the life expectancy of three months or more, who were experiencing cancer-related pain with a worst severity of at least 4 on a 0-10 scale despite a trial of at least one opioid and appropriate adjuvant analgesic, received two subcutaneous infusions at least a week apart; lidocaine 10 mg/kg over 5.5 hours and saline placebo. The primary outcome was either a reduction in worst pain intensity of two points out of 10 or a reduction in 24 hours opioid dose of at least 30% without worsening of pain scores, in seven days. The SCLI was only effective for two subjects. One of these subjects experienced a drop in worst pain score and the other experienced a reduction in opioid dose. A weight-based subcutaneous infusion of lidocaine does not achieve sufficiently predictable blood levels for determining lidocaine responsiveness. This study does not allow any conclusion to be drawn on whether or not lidocaine would have been more effective had it been titrated to higher blood levels.
Learn More >African-American older adults, particularly those who live in economically deprived areas, are less likely to receive pain and psychotropic medications, compared to Whites. This study explored the link between social, behavioral, and health correlates of pain and psychotropic medication use in a sample of economically disadvantaged African-American older adults. This community-based study recruited 740 African-American older adults who were 55+ yeas-old in economically disadvantaged areas of South Los Angeles. Opioid-based and psychotropic medications were the outcome variables. Gender, age, living arrangement, socioeconomic status (educational attainment and financial strain), continuity of medical care, health management organization membership, sleeping disorder/insomnia, arthritis, back pain, pain severity, self-rated health, depressive symptoms, and major chronic conditions were the explanatory variables. Logistic regression was used for data analyses. Arthritis, back pain, severe pain, and poor self-rated health were associated with opioid-based medications. Pain severity and depressive symptoms were correlated with psychotropic medication. Among African-American older adults, arthritis, back pain, poor self-rated health, and severe pain increase the chance of opioid-based and psychotropic medication. Future research should test factors that can reduce inappropriate and appropriate use and prescription of opioid-based and psychotropic medication among economically disadvantaged African-American older adults.
Learn More >MT-45 is a synthetic opioid that was developed in the 1970s as an analgesic compound. However, in recent years MT-45 has been associated with multiple deaths in Europe and has been included in the class of novel psychoactive substances known as novel synthetic opioids (NSOs). Little is known about the pharmaco-toxicological effects of MT-45. Therefore, we used a dynamic mass redistribution (DMR) assay to investigate the pharmacodynamic profile of this NSO in vitro compared with morphine. We then used in vivo studies to investigate the effect of the acute systemic administration of MT-45 (0.01-15 mg/kg i.p.) on motor and sensorimotor (visual, acoustic and tactile) responses, mechanical and thermal analgesia, muscle strength and body temperature in CD-1 male mice. Higher doses of MT-45 (6-30 mg/kg i.p.) were used to investigate cardiorespiratory changes (heart rate, respiratory rate, SpO saturation and pulse distention). All effects of MT-45 were compared with those of morphine. In vitro DMR assay results demonstrated that at human recombinant opioid receptors MT-45 behaves as a potent selective mu agonist with a slightly higher efficacy than morphine. In vivo results showed that MT-45 progressively induces tail elevation at the lowest dose tested (0.01 mg/kg), increased mechanical and thermal antinociception (starting from 1 to 6 mg/kg), decreased visual sensorimotor responses (starting from 3 to 6 mg/kg) and reduced tactile responses, modulated motor performance and induced muscle rigidity at higher doses (15 mg/kg). In addition, at higher doses (15-30 mg/kg) MT-45 impaired the cardiorespiratory functions. All effects were prevented by the administration of the opioid receptor antagonist naloxone. These findings reveal the risks associated with the ingestion of opioids and the importance of studying these drugs and undertaking more clinical studies of the current molecules to better understand possible therapeutic interventions in the case of toxicity.
Learn More >Low back and lower extremity pain have been treated since 1901 with local anesthetics alone and since 1952 in combination with steroids. Over the years, multiple randomized controlled trials, systematic reviews with or without meta-analysis have been reaching discordant conclusions regarding the effectiveness of sodium chloride solution, local anesthetics, and steroids in managing spinal pain. Further, related to lack of understanding, multiple reviewers have considered local anesthetics including lidocaine and bupivacaine as equivalent to placebo based on theory that steroid is the only drug effective in the epidural space. In this review, we assessed effectiveness of epidurally administered bupivacaine with or without steroids to rule out misconceptions of placebo and to show the comparative effectiveness of epidural bupivacaine alone compared to epidural bupivacaine with steroids.
Learn More >The world is currently dominated by the Corona Virus Disease 2019 (COVID-19) pandemic. Besides the obvious concerns about limitation of virus spread and providing the best possible care to infected patients, a concomitant concern has now arisen in view of a putative link between the use of certain drugs, such as Renin-Angiotensin System (RAS) inhibitors and ibuprofen, and an increased risk for COVID-19 infection. We here discuss this concern in relation to headache treatment and conclude that, based on current evidence, there is no reason to abandon treatment of headache patients with RAS inhibitors or ibuprofen.
Learn More >Treatment with onabotulinumtoxin A (BT-A) is safe and effective for chronic migraine (CM). Several studies assessed possible predictors of response to treatment with BT-A, but there is little knowledge on the frequency and predictors of sustained response. The aim of this study was to evaluate sustained response to BT-A in patients with CM.
Learn More >A systematic review and meta-analysis of randomised controlled trials was undertaken to evaluate the effect of intrathecal dexmedetomidine (DEX) on the duration of postoperative analgesia, postoperative pain scores and incidences of adverse effects. Databases and Data Treatment: Database search was performed from inception until January 2019. All randomised controlled trials analysing acute postoperative pain characteristics after intrathecal DEX administration in adults undergoing spinal anaesthesia for elective surgery were included. The primary outcome was postoperative analgesic duration, defined as the time to first analgesic request. The secondary outcomes included pain scores at 6, 12, and 24 post-operative hours and rates of hypotension, bradycardia, shivering and postoperative nausea and vomiting.
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