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When treating migraine patients in the current era of Coronavirus Disease 2019 (COVID-19), many institutions have moved away from face-to-face procedures like onabotulinumtoxinA injections, sometimes transitioning to the newer CGRP antibodies for migraine prevention. However, despite our best efforts to mitigate viral transmission, many of our migraine patients may eventually be exposed to SARS-CoV2. While most patients will have mild to moderate symptoms, a subset will become severely ill, with possible complications including respiratory failure and acute respiratory distress syndrome (ARDS). Given the possibility of this level of severe respiratory illness, we should consider what effect blocking calcitonin gene-related peptide (CGRP) might have on these patients.
Learn More >The opioid epidemic has plagued the United States with high levels of abuse and poor quality of life for chronic pain patients requiring continuous use of opioids. New drug discovery efforts have been implemented to mitigate this epidemic, however, new medications are still limited by low efficacy and/or high side effect and abuse potential. Intermittent fasting (IF) has recently been shown to improve a variety of pathological states, including stroke and neuroinflammation. Numerous animal and human studies have shown the benefits of IF in these disease states, but not in pain and opioid treatment. We thus subjected male and female CD-1 mice to 18-hour fasting intervals followed by 6-hour feed periods with standard chow for 1 week. Mice which underwent this diet displayed an enhanced anti-nociceptive response to morphine both in efficacy and duration using thermal tail flick and post-operative paw incision pain models. While showing enhanced anti-nociception, IF mice also demonstrated no morphine reward and reduced tolerance and constipation. Seeking a mechanism for these improvements, we found that the mu opioid receptor (MOR) showed enhanced efficacy and reduced tolerance in the spinal cord and periaqueductal grey (PAG) respectively from IF mice using a S-GTPγS coupling assay. These improvements in receptor function were not due to changes in MOR protein expression. These data suggest that a daily IF diet may improve the therapeutic index of acute and chronic opioid therapies for pain patients in the clinic, providing a novel tool to improve patient therapy and reduce potential abuse.
Learn More >Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into presynaptic terminals via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat both depression and pain, and therapeutic effects by these compounds often require repeated treatment for days or weeks.
Learn More >Platinum-based chemotherapeutics still play an important role in cancer therapy, however, severe side effects, such as painful neuropathy, occur frequently. The pathophysiologic mechanisms depend on the applied chemotherapeutic agent and are still controversial. In addition to neuronal damage, disturbance of glial cell activity may contribute to neurotoxicity. Here, we focused on the effect of oxaliplatin on satellite glial cell (SGC) function and on the activity of the dorsal root ganglion (DRG) neurons. SGCs were isolated as high-purity cultures and treated with 1 and 10 μM oxaliplatin for 2, 4 and 24 h. Subsequently, glial fibrillary acid protein (GFAP), reactive oxygen species (ROS), Connexin-43 (Cx-43), and inward rectifier potassium channel 4.1 (K) expression was determined by immunocytochemical staining (ICC) and Western blot analyses. Immunochemical staining and Western blot analysis showed an increase in the immune reactivity (IR) and protein levels of ROS, GFAP, and Cx-43. Furthermore, reduction of the IR and protein levels and current density were demonstrated using patch-clamp measurements, of K channels after oxaliplatin exposure. Cytokine release in SGCs was measured using enzyme-linked immunosorbent assays (ELISA) after oxaliplatin exposure and indicated an increased release of IL-6 and TNFα, while IL-1β was decreased. The direct influence of SGC-secreted factors in the supernatant after oxaliplatin treatment led to the hyperexcitability of cultured DRG neurons. In summary, oxaliplatin has a direct impact on the modulation and function of different SGC proteins. Furthermore, SGC-released factors influence the excitability of sensory neurons, qualifying SGCs as potential targets for the prevention and treatment of oxaliplatin-induced polyneuropathy.
Learn More >Despite similar distribution patterns and intracellular events observed in the nociceptin/orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and non-peptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptorrelated ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.
Learn More >High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, facilitates pain signals as well as inflammation. Intraplantar or intraspinal application of HMGB1 elicits hyperalgesia/allodynia in rodents by activating the advanced glycosylation end-product specific receptor (receptor for advanced glycation end-products; RAGE) or Toll-like receptor 4 (TLR4). Endogenous HMGB1 derived from neurons, perineuronal cells or immune cells accumulating in the dorsal root ganglion or sensory nerves participates in somatic and visceral pain consisting of neuropathic and/or inflammatory components. Endothelial thrombomodulin (TM) and recombinant human soluble TM, TMα, dramatically promote thrombin-dependent degradation of HMGB1, and systemic administration of TMα prevents and reverses various HMGB1-dependent pathological pain. Small molecules that directly inactivate HMGB1 or antagonize HMGB1-targeted receptors would be useful to reduce various intractable pain. Thus, HMGB1 and its receptors are considered to serve as promising targets in developing novel agents to prevent or treat pathological pain.
Learn More >Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-γ activation prevents pain and inflammation in the temporomandibular joint (TMJ) by decreasing cytokine release and stimulating the synthesis of endogenous opioids. The goal of this study was to clarify whether PPAR-γ activation induces macrophage polarization, inhibiting inflammatory cytokine release and leukocyte recruitment. In addition, we investigated the involvement of heme oxygenase 1 (HO-1) in downstream events after PPAR-γ activation. Our results demonstrate that PPAR-γ activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ induces the PPAR-γ heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-γ activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca/calmodulin expression did not change after PPAR-γ activation indicating that is not required for the activation of the intracellular L-arginine/NO/cGMP/K channel pathway. In summary, the anti-inflammatory actions induced by PPAR-γ activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.
Learn More >Ketamine and Magnesium for Refractory Neuropathic Pain: A Randomized, Double-blind, Crossover Trial.
Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks.
Learn More >Morphine and other opioids are commonly used to treat pain despite their numerous adverse side effects. Modulating μ-opioid receptor (MOR) signaling is one way to potentially improve opioid therapy. In mice, the chaperone protein Hsp90 mediates MOR signaling within the brain. Here, we found that inhibiting Hsp90 specifically in the spinal cord enhanced the antinociceptive effects of morphine in mice. Intrathecal, but not systemic, administration of the Hsp90 inhibitors 17-AAG or KU-32 amplified the effects of morphine in suppressing sensitivity to both thermal and mechanical stimuli in mice. Hsp90 inhibition enabled opioid-induced phosphorylation of the kinase ERK and increased abundance of the kinase RSK in the dorsal horns of the spinal cord, which are heavily populated with primary afferent sensory neurons. The additive effects of Hsp90 inhibition were abolished upon intrathecal inhibition of ERK, RSK, or protein synthesis. This mechanism downstream of MOR, localized to the spinal cord and repressed by Hsp90, may potentially be used to enhance the efficacy and presumably decrease the side effects of opioid therapy.
Learn More >Voltage gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic SAR studies carried out to identify novel sulfonamide derivatives as potent, selective and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5 and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43 and 51 have shown favorable PK profile across different species and robust efficacy in veratridine and formalin induced inflammatory pain models in mice. Compound 51 has also shown significant effect in CCI induced neuropathic pain model. Profile of 51 has indicated that it has the potential for further evaluation as a therapeutic for pain.
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