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The "gepants" are a class of calcitonin gene-related peptide (CGRP) receptor antagonist molecules that have been developed for the prevention and treatment of migraine. Rimegepant is reported to act at the CGRP receptor, has good oral bioavailability, and has had positive clinical trial results. However, there is very little data available describing its receptor pharmacology. Importantly, rimegepant activity at the AMY receptor, a second potent CGRP receptor that is known to be expressed in the trigeminovascular system, has not been reported. The ability of rimegepant to antagonize activation of human CGRP, AMY, and related adrenomedullin receptors was determined in transfected in Cos7 cells. Rimegepant was an effective antagonist at both the CGRP and AMY receptor. The antagonism of both CGRP and AMY receptors may have implications for our understanding of the mechanism of action of rimegepant in the treatment of migraine.
Learn More >Interstitial cystitis/bladder pain syndrome (IC) is a debilitating condition of chronic pelvic pain with unknown etiology. Recently, we used a genetic approach in a murine model of IC to identify the lipase acyloxyacyl hydrolase (AOAH) as a modulator of pelvic pain. We found that AOAH-deficient mice have elevated pelvic pain responses, and AOAH immunoreactivity was detected along the bladder-brain axis. Lipidomic analyses identified arachidonic acid (AA) and its metabolite PGE2 as significantly elevated in the sacral spinal cord of AOAH-deficient mice, suggesting AA is a substrate for AOAH. Here, we quantified the effects of AOAH on phospholipids containing AA. Spinal cord lipidomics revealed increased AA-containing phosphatidylcholine in AOAH-deficient mice and concomitantly decreased AA-phosphatidylethanolamine, consistent with decreased CoA-independent transferase activity (CoIT). Overexpression of AOAH in cell cultures similarly altered distribution of AA in phospholipid pools, promoted AA incorporation, and resulted in decreased membrane fluidity. Finally, administration of a PGE2 receptor antagonist reduced pelvic pain in AOAH-deficient mice. Together, these findings suggest that AOAH represents a potential CoA-independent AA transferase that modulates CNS pain pathways at the level of phospholipid metabolism.
Learn More >Anti-GD2 therapy with dinutuximab is effective in improving the survival of high-risk neuroblastoma patients in remission and after relapse. However, allodynia is the major dose-limiting side effect, hindering its use for neuroblastoma patients at higher doses and for other GD2-expressing malignancies. As polyamines can enhance neuronal sensitization, including development of allodynia and other forms of pathological pain, we hypothesized that polyamine depletion might prove an effective strategy for relief of anti-GD2 induced allodynia.
Learn More >As a field, psychiatry is undergoing an exciting paradigm shift toward early identification and intervention that will likely minimize both the burden associated with severe mental illnesses as well as their duration. In this context, the rapid-acting antidepressant ketamine has revolutionized our understanding of antidepressant response and greatly expanded the pharmacologic armamentarium for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response support a growing emphasis on early identification, which would allow clinicians to identify biologically enriched subgroups with treatment-resistant depression who are more likely to benefit from ketamine therapy. This chapter presents a broad overview of a range of translational biomarkers, including those drawn from imaging and electrophysiological studies, sleep and circadian rhythms, and HPA axis/endocrine function as well as metabolic, immune, (epi)genetic, and neurotrophic biomarkers related to ketamine response. Ketamine's unique, rapid-acting properties may serve as a model to explore a whole new class of novel rapid-acting treatments with the potential to revolutionize drug development and discovery. However, it should be noted that although several of the biomarkers reviewed here provide promising insights into ketamine's mechanism of action, most studies have focused on acute rather than longer-term antidepressant effects and, at present, none of the biomarkers are ready for clinical use.
Learn More >An imbalance in perioperative cytokine response may cause acute pain and postoperative complications. Anesthetic drugs modulate this cytokine response, but their role in non-major breast cancer surgery is unclear. In an exploratory study, we investigated whether intravenous lidocaine and dexamethasone could modulate the cytokine response into an anti-inflammatory direction. We also evaluated interrelationships between cytokine levels, pain scores and postoperative complications. Our goal is to develop multimodal analgesia regimens optimizing outcome after breast cancer surgery.
Learn More >Dihydroergotamine (DHE) is an ergot alkaloid derivative of substances produced by rye fungus. Ergotamine was first used in the field of gynecology and obstetrics, then used for migraine treatment a few years later. DHE was developed as a derivative of ergotamine. DHE, when compared to ergotamine, demonstrates greater alpha-adrenergic antagonist activity, lower arterial vasoconstriction, less dopaminergic agonism, and lower emetic potential. DHE can be delivered via several routes including intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (IN), oral, and orally inhaled (although the latter two are not available in the USA and the last remains experimental only). DHE can be used in an outpatient basis in infusion centers, emergency departments, and urgent care centers, as well as inpatient treatment for admitted patients. There are protocols for adults as well as pediatric migraine treatment. DHE and other ergot alkaloids are considered contraindicated in pregnant women as they decrease uterine blood flow and increase uterine muscle contractility predisposing to spontaneous abortion. DHE during lactation is also not recommended as it can lead to gastrointestinal distress and weakness in infants; it can also suppress milk production. Caution should be taken before administering DHE in patients with cardiovascular risk factors. DHE is an older drug with an interesting history, yet it is still clinically useful today for patients with migraine attacks not responsive to triptans, who have a greater burden from migraine, and in refractory migraine.
Learn More >The specific serotonin type 3 (5-HT)-receptor antagonist granisetron effectively reduces clinical as well as experimental muscle pain and hyperalgesia and with a duration that exceeds that of lidocaine. Hence, it may be an alternative to lidocaine as a local anesthetic. There are also some indications that granisetron in addition to 5-HT receptors blocks sodium channels. Thus, the local anesthetic effect by granisetron may resemble that of lidocaine, but this has not been tested. The aim of this study was therefore to compare the effect granisetron has on facial skin sensitivity to the effect of lidocaine and isotonic saline. This was a randomized, controlled, and double-blind study, in which 1 ml of either granisetron (test-substance), lidocaine (positive control), or isotonic saline (negative control) was injected into the skin over the masseter muscle at three different occasions in 18 healthy males (27.2 ± 5.8 years old). Skin detection thresholds and pain thresholds for thermal stimuli as well as mechanical detection thresholds and sensitivity to a painful mechanical (pinprick) stimulus were assessed before (baseline) and 5, 20, 40, and 60 min after injection. The quality and area of subjective sensory change over the cheek were assessed 20 min after injection. All substances increased the mechanical detection threshold (granisetron: = 0.011; lidocaine: = 0.016; saline: = 0.031). Both granisetron and lidocaine, but not isotonic saline, increased the heat detection thresholds ( < 0.001 and < 0.02, respectively), but not the cold detection thresholds. Granisetron and lidocaine also reduced pinprick pain ( = 0.001 for each comparison). There were no significant differences between granisetron and lidocaine for any of these variables. There was no effect on thermal pain thresholds for any substance. The similar analgesic patterns on mechanical sensory and pain thresholds as well as thermal sensory thresholds over the facial skin by subcutaneous injection of granisetron and lidocaine shown in this study and the absence of paresthesia, in combination with the reduced pain intensity and pressure pain sensitivity shown in previous studies, indicate that granisetron might be a novel candidate as a local anesthetic.
Learn More >Opioid receptors comprise μ (MOP), δ (DOP), κ (KOP), and nociceptin/orphanin FQ (NOP) receptors. Opioids are agonists of MOP, DOP, and KOP receptors, whereas nociceptin/orphanin FQ (N/OFQ) is an agonist of NOP receptors. Activation of all four opioid receptors in neurons can induce analgesia in animal models, but the most clinically relevant are MOP receptor agonists (e.g., morphine, fentanyl). Opioids can also affect the function of immune cells, and their actions in relation to immunosuppression and infections have been widely discussed. Here, we analyze the expression and the role of opioid receptors in peripheral immune cells and glia in the modulation of pain. All four opioid receptors have been identified at the mRNA and protein levels in immune cells (lymphocytes, granulocytes, monocytes, macrophages) in humans, rhesus monkeys, rats or mice. Activation of leukocyte MOP, DOP, and KOP receptors was recently reported to attenuate pain after nerve injury in mice. This involved intracellular Ca-regulated release of opioid peptides from immune cells, which subsequently activated MOP, DOP, and KOP receptors on peripheral neurons. There is no evidence of pain modulation by leukocyte NOP receptors. More good quality studies are needed to verify the presence of DOP, KOP, and NOP receptors in native glia. Although still questioned, MOP receptors might be expressed in brain or spinal cord microglia and astrocytes in humans, mice, and rats. Morphine acting at spinal cord microglia is often reported to induce hyperalgesia in rodents. However, most studies used animals without pathological pain and/or unconventional paradigms (e.g., high or ultra-low doses, pain assessment after abrupt discontinuation of chronic morphine treatment). Therefore, the opioid-induced hyperalgesia can be viewed in the context of dependence/withdrawal rather than pain management, in line with clinical reports. There is convincing evidence of analgesic effects mediated by immune cell-derived opioid peptides in animal models and in humans. Together, MOP, DOP, and KOP receptors, and opioid peptides in immune cells can ameliorate pathological pain. The relevance of NOP receptors and N/OFQ in leukocytes, and of all opioid receptors, opioid peptides and N/OFQ in native glia for pain control is yet to be clarified.
Learn More >Transcranial direct current stimulation (tDCS) is used for various chronic pain conditions, but experience with tDCS for acute postoperative pain is limited. This study investigated the effect of tDCS vs. sham stimulation on postoperative morphine consumption and pain intensity after thoracotomy.
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