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The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus co-treated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone anti-nociception in all models by 54.7%-628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, and D24M had a mild transient effect in the Rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced anti-nociception using small molecule inhibitors (KN93, Src-I1). Together these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs via the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
Learn More >Research on intersectionality and chronic pain disparities is very limited. Intersectionality explores the interconnections between multiple aspects of identity and provides a more accurate picture of disparities. This study applied a relatively novel statistical approach (i.e., Latent Class Analysis; LCA) to examine chronic pain disparities with an intersectional identity approach. Cross-sectional data were analyzed using pre-treatment data from the Learning About My Pain (LAMP) trial, a randomized comparative effectiveness study of group-based psychosocial interventions (PCORI Contract #941, Beverly Thorn, PI; clinicaltrials.gov identifier NCT01967342) for patients receiving care for chronic pain at low-income clinics in rural and suburban Alabama. LCA results suggested a 5-class model. In order to easily identify each class, the following labels were created: Older Adults (OA), Younger Adults (YA), Severe Disparity (SD), Older/Black/African-American (OB), and Working Women (WW). The latent disparity classes varied by pre-treatment chronic pain functioning. Overall, the SD group had the lowest levels of functioning, and the WW group had the highest levels of functioning. Although younger and with higher literacy levels, the YA group had similar levels of pain interference and depressive symptoms to the SD group (p's < .05). The YA group also had higher pain catastrophizing than the OA group (p < .005). Results highlighted the importance of the interactions between the multiple factors of socioeconomic status, age, and race in the experience of chronic pain. The intersectional identity theory approach through LCA provided an integrated picture of chronic pain disparities in a highly understudied and underserved population.
Learn More >Peripheral nerve injuries result in pronounced alterations in dorsal root ganglia (DRG), which can lead to the development of neuropathic pain. Although the polymodal mechanosensitive transient receptor potential ankyrin 1 ion channel (TRPA1) is emerging as a relevant target for potential analgesic therapies, preclinical studies do not provide unequivocal mechanistic insight into its relevance for neuropathic pain pathogenesis. By utilizing a transgenic mouse model with a conditional depletion of the interleukin-6 signal transducer gp130 in Nav1.8 expressing neurons (SNS-gp130-/-), we provide a mechanistic regulatory link between IL-6/gp130 and TRPA1 in the spared nerve injury model (SNI). SNI mice developed profound mechanical hypersensitivity as indicated by increased responses in the von Frey behavioral test in vivo, as well as a significant increase in mechanosensitivity of unmyelinated nociceptive primary afferents in ex vivo skin nerve recordings. In contrast to wild type and control gp130fl/fl animals, SNS-gp130-/- mice did not develop mechanical hypersensitivity after SNI and exhibited low levels of Trpa1 mRNA in sensory neurons, which were partially restored by adenoviral gp130 re-expression in vitro. Importantly, uninjured but not injured neurons developed increased responsiveness to the TRPA1 agonist cinnamon aldehyde (CA), and neurons derived from SNS-gp130-/- mice after SNI were significantly less responsive to CA. Our study shows for the first time that TRPA1 upregulation is attributed specifically to uninjured neurons in the SNI model and this depended on the IL-6 signal transducer gp130. We provide a solution to the enigma of TRPA1 regulation following nerve injury and stress its significance as an important target for neuropathic pain disorders.
Learn More >and loss-of-function mutations in Nav1.7 cause chronic pain and pain insensitivity, respectively. The preferential expression of Nav1.7 in peripheral nervous system and its role in human pain signaling make Nav1.7 a promising target for next-generation pain therapeutics. However, pharmacological agents have not fully recapitulated these pain phenotypes, and, due to the lack of subtype-selective molecular modulators, the role of Nav1.7 in the perception of pain remains poorly understood. Scorpion venom is an excellent source of bioactive peptides that modulate various ion channels, including voltage-gated sodium (Nav) channels . Here, we demonstrate that Buthus martensii Karsch scorpion venom (BV) elicits pain responses in mice through direct enhancement of Nav1.7 activity, and have identified that Makatoxin-3, an α-like toxin as a critical component for BV-mediated effects on Nav1.7. Blocking other Nav subtypes did not eliminate BV-evoked pain responses, supporting the pivotal role of Nav1.7 in BV-induced pain . Makatoxin-3 acts on the S3-S4 loop of voltage sensor domain IV (VSD4) of Nav1.7, which causes a hyperpolarizing shift in the steady-state fast inactivation and impairs inactivation kinetics. We also determined the key residues and structure-function relationships for the toxin-channel interactions, which are distinct from those of other well-studied α-toxins. This study not only reveals a new mechanism underlying BV-evoked pain, but also enriches our knowledge of key structural elements of scorpion toxins that are pivotal for toxin-Nav1.7 interaction, which facilitates the design of novel Nav1.7 selective modulators.
Learn More >Group I metabotropic glutamate receptors (mGluR1 and mGluR5, mGluR1/5) have been implicated in several CNS diseases including chronic pain. It is known that activation of mGluR1/5 results in production of inositol triphosphate (IP3) and diacylglycerol (DAG) that leads to activation of extracellular signal-regulated kinases (ERK1/2) and an increase in neuronal excitability, but how mGluR1/5 mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry (SOCE) and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that mGluR1/5 recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by NMDA or AMPA receptors. Glutamate-induced Ca2+ entry in the presence of NMDA/AMPA receptor antagonists is eliminated in Orai1-deficient neurons. DHPG (an agonist of mGluR1/5)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of TRPC1 or TRPC3. DHPG-induced activation of ERK1/2 and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and mGluR1/5 and shed light on the mechanism underlying mGluR1/5-mediated neuronal plasticity.
Learn More >Dietary interventions are promising approaches to treat pain associated with metabolic changes because they impact both metabolic and neural components contributing to painful neuropathy. Here, we tested whether consumption of a ketogenic diet could affect sensation, pain, and epidermal innervation loss in type 1 diabetic mice. C57Bl/6 mice were rendered diabetic using streptozotocin and administered a ketogenic diet at either three weeks (prevention) or nine weeks (reversal) of uncontrolled diabetes. We quantified changes in metabolic biomarkers, sensory thresholds, and epidermal innervation to assess impact on neuropathy parameters. Diabetic mice consuming ketogenic diet had normalized weight gain, reduced blood glucose, elevated blood ketones, and reduced hemoglobin-A1C levels. These metabolic biomarkers were also improved following nine weeks of diabetes followed by four weeks of a ketogenic diet. Diabetic mice fed a control chow diet developed rapid mechanical allodynia of the hind paw that was reversed within a week of consumption of a ketogenic diet in both prevention and reversal studies. Loss of thermal sensation was also improved by consumption of a ketogenic diet via normalized thermal thresholds. Finally, diabetic mice consuming a ketogenic diet had normalized epidermal innervation, including after nine weeks of uncontrolled diabetes and four weeks of consumption of the ketogenic diet. These results suggest that, in mice, a ketogenic diet can prevent and reverse changes in key metabolic biomarkers, altered sensation, pain and axon innervation of the skin. These results identify a ketogenic diet as a potential therapeutic intervention for patients with painful diabetic neuropathy and/or epidermal axon loss.
Learn More >Ketamine is often used in pain clinics for refractory chronic pain, but its long-term efficacy is poorly reported. The main objective was to assess the long-term effect of ketamine on pain and health variables in patients with refractory chronic pain.A prospective, multicenter, one-year follow-up observational study (NCT03319238) was conducted in thirty French pain clinics where ketamine is commonly prescribed. This study focused on patients with one ketamine delivery procedure (n=256). The primary endpoint was pain intensity (0-10 numerical pain rating scale) before and after ketamine every month for one year. Secondary outcomes aimed to identify pain trajectories by semi-parametric mixture models and to collect adverse events.The following data were obtained for 256 patients: pain intensity decreased significantly (6.8±1.8, n=240 at baseline versus 5.7±1.8, n=93 at 12 months, p<0.001). The effect size of the main endpoint was 0.61 (95%CI: [0.40; 0.80]; p<0.001). Three pain trajectories were identified: 16.0% of patients in "mild pain" (mostly neuropathic pain), 35.3% in "moderate pain" and 45.7% in "severe pain" (mostly fibromyalgia) trajectory. Neuropathic pain and fibromyalgia presented opposite outcomes, pain severity being associated with anxiety, depression and a poorer quality of life. Adverse events occurred at one week in 108/218 [50%] patients and this rate gradually decreased throughout the follow-up.This real-life study in chronic pain identified distinct pain trajectories and predictive variables of ketamine efficacy. It is now pivotal to further study and optimize the subtyping of patients to provide the most effective and safe ketamine treatment in this vulnerable population.
Learn More >Migraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach.
Learn More >Fibromyalgia (FM) is a condition of chronic widespread pain (CWP) that can occur throughout the life cycle and is likely underrecognized in older patients. FM is associated with considerable suffering and reduction in quality of life and may occur as a unique condition, but in older patients is most likely to be associated with another medical illness. Understood mechanistically to be a sensitization of the nervous system, recently identified as nociplastic pain, FM is accepted as a valid medical illness that requires a positive diagnosis and directed treatments. The cornerstone of treatments for FM are nonpharmacologic interventions, with the understanding that medications provide only modest benefit for most patients, and with particular concern about adverse effects in older patients. If FM is not recognized, treatments may be misdirected to the other medical condition, with failure to address FM symptoms, leading to overall poor outcome. In contrast, new complaints in older patients should not immediately be attributed to FM, and physicians should be vigilant to ensure that onset of a new illness is not ignored. As FM is most often a lifelong condition, patients should be encouraged to identify their own personal strategies that can attenuate symptoms, especially when symptoms flare. Continued life participation should be the outcome goal.
Learn More >Transient receptor potential vanilloid member 1 (TRPV1) is a Ca-permeable cation channel that serves as the primary heat and capsaicin sensor in humans. Using cryo-EM, we have determined the structures of apo and capsaicin-bound full-length rat TRPV1 reconstituted into lipid nanodiscs over a range of temperatures. This has allowed us to visualize the noxious heat-induced opening of TRPV1 in the presence of capsaicin. Notably, noxious heat-dependent TRPV1 opening comprises stepwise conformational transitions. Global conformational changes across multiple subdomains of TRPV1 are followed by the rearrangement of the outer pore, leading to gate opening. Solvent-accessible surface area analyses and functional studies suggest that a subset of residues form an interaction network that is directly involved in heat sensing. Our study provides a glimpse of the molecular principles underlying noxious physical and chemical stimuli sensing by TRPV1, which can be extended to other thermal sensing ion channels.
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