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Cortical spreading depression (CSD) is a propagating wave of depolarization followed by depression of cortical activity. CSD triggers neuroinflammation via the pannexin-1 (Panx1) channel opening, which may eventually cause migraine headaches. However, the regulatory mechanism of Panx1 is unknown. This study investigates whether sarcoma family kinases (SFK) are involved in transmitting CSD-induced Panx1 activation, which is mediated by the NR2A-containing N-methyl-D-aspartate receptor. CSD was induced by topical application of K to cerebral cortices of rats and mouse brain slices. SFK inhibitor, PP2, or NR2A-receptor antagonist, NVP-AAM077, was perfused into contralateral cerebral ventricles (i.c.v.) of rats prior to CSD induction. Co-immunoprecipitation and Western blot were used for detecting protein interactions, and histofluorescence for addressing Panx1 activation. The results demonstrated that PP2 attenuated CSD-induced Panx1 activation in rat ipsilateral cortices. Cortical susceptibility to CSD was reduced by PP2 in rats and by TAT-Panx308 that disrupts SFK-Panx1 interaction in mouse brain slices. Furthermore, CSD promoted activated SFK coupling with Panx1 in rat ipsilateral cortices. Moreover, inhibition of NR2A by NVP-AAM077 reduced elevation of ipsilateral SFK-Panx1 interaction, Panx1 activation induced by CSD and cortical susceptibility to CSD in rats. These data suggest NR2A-regulated, SFK-dependent Panx1 activity plays an important role in migraine aura pathogenesis.
Learn More >The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats. On day 3 after NPLA administration, the MHWT recovered considerably in IANX rats. Following L-arginine injection into the TG, the MHWT was significantly reduced within 15 min, and the mean number of TG cells encircled by glial fibrillary acidic protein (GFAP)-IR cells was substantially higher. The relative number of nNOS-IR cells encircled by GFAP-IR cells was significantly increased in IANX rats. In contrast, after NPLA injection into the TG, the relative number of GFAP-IR cells was considerably reduced in IANX rats. Fluorocitrate administration into the TG significantly reduced the number of GFAP-IR cells and prevented the MHWT reduction in IANX rats. The present findings suggest that following IANX, satellite glial cells are activated via nitric oxide (NO) signaling from TG neurons. The spreading satellite glial cell activation within the TG results in mechanical hypersensitivity of face regions not directly associated with the trigeminal nerve injury.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients.
Learn More >Skeletal pathologies are often accompanied by bone pain, which has negative effects on the quality of life and functional status of patients. Bone pain can be caused by a wide variety of injuries and diseases including (poorly healed) fractures, bone cancer, osteoarthritis and also iatrogenic by skeletal interventions. Orthopedic interventions are considered to be the most painful surgical procedures overall. Two major groups of medication currently used to attenuate bone pain are NSAIDs and opioids. However, these systemic drugs frequently introduce adverse events, emphasizing the need for alternative therapies that are directed at the pathophysiological mechanisms underlying bone pain. The periosteum, cortical bone and bone marrow are mainly innervated by sensory A-delta fibers and C-fibers. These fibers are mostly present in the periosteum rendering this structure most sensitive to nociceptive stimuli. A-delta fibers and C-fibers can be activated upon mechanical distortion, acidic environment and increased intramedullary pressure. After activation, these fibers can be sensitized by inflammatory mediators, phosphorylation of acid-sensing ion channels and cytokine receptors, or by upregulation of transcription factors. This can result in a change of pain perception such that normally non-noxious stimuli are now perceived as noxious. Pathological conditions in the bone can produce neurotrophic factors that bind to receptors on A-delta fibers and C-fibers. These fibers then start to sprout and increase the innervation density of the bone, making it more sensitive to nociceptive stimuli. In addition, repetitive painful stimuli cause neurochemical and electrophysiological alterations in afferent sensory neurons in the spinal cord, which leads to central sensitization, and can contribute to chronic bone pain. Understanding the pathophysiological mechanisms underlying bone pain in different skeletal injuries and diseases is important for the development of alternative, targeted pain treatments. These pain mechanism-based alternatives have the potential to improve the quality of life of patients suffering from bone pain without introducing undesirable systemic effects.
Learn More >There are adverse effects associated with long-term opioid therapy (LTOT) for chronic pain and clinicians infrequently adhere to opioid treatment guideline recommendations for reducing risk and mitigating opioid-related harms. The primary goal of the Improving the Safety of Opioid Therapy (ISOT) intervention is to reduce harms related to prescription opioids. Secondary aims focus on enhancing the clinician-patient relationship and not having a negative impact on pain-related outcomes (to be examined through a non-inferiority analysis). The study is a cluster-randomized trial and the 44 primary care providers (PCPs) who enrolled were randomized to receive either (1) a two-hour educational workshop about a patient-centered approach to opioid therapy or (2) the educational workshop plus a collaborative care intervention delivered by a nurse care manager (NCM). Patients were assigned to the same condition as their treating PCP. ISOT was based on the chronic care model and include patient and provider activation, outcomes monitoring, and feedback to the PCP over 12 months. The NCM conducted a baseline assessment with intervention patients, tracked opioid-related behaviors and outcomes, and provided decision support to the opioid-prescribing clinician about opioid safety. Between June 2016 and October 2018, 293 veterans who were prescribed LTOT for chronic pain were enrolled, completed a baseline assessment, and assigned to a treatment condition. Participants were enrolled for 12 months. Masked assessments were conducted with participants at baseline, 6-months, and 12-months. This manuscript describes study rationale, research methods, and baseline findings.
Learn More >In the pain matrix, the insular cortex (IC) is mainly involved in discriminative sensory and motivative emotion. Abnormal signal transmission from injury site causes neuropathic pain, which generates enhanced synaptic plasticity. The mammalian target of rapamycin (mTOR) complex is the key regulator of protein synthesis; it is involved in the modulation of synaptic plasticity. To date, there has been no report on the changes in optical signals in the IC under neuropathic condition after treatment with mTOR inhibitors, such as Torin1 and XL388. Therefore, we aimed to determine the pain-relieving effect of mTOR inhibitors (Torin1 and XL388) and observe the changes in optical signals in the IC after treatment. Mechanical threshold was measured in adult male Sprague-Dawley rats after neuropathic surgery, and therapeutic effect of inhibitors was assessed on post-operative day 7 following the microinjection of Torin1 or XL388 into the IC. Optical signals were acquired to observe the neuronal activity of the IC in response to peripheral stimulation before and after treatment with mTOR inhibitors. Consequently, the inhibitors showed the most effective alleviation 4 h after microinjection into the IC. In optical imaging, peak amplitudes of optical signals and areas of activated regions were reduced after treatment with Torin1 and XL388. However, there were no significant optical signal changes in the IC before and after vehicle application. These findings suggested that Torin1 and XL388 are associated with the alleviation of neuronal activity that is excessively manifested in the IC, and is assumed to diminish synaptic plasticity.
Learn More >To investigate the number and characteristics of the Spanish population affected by headache disorders and the direct medical cost that these patients represent for the healthcare system.
Learn More >: Migraine is a chronic neurovascular disorder characterized by recurrent headache attacks associated with neurological and autonomic symptoms. The pathophysiological mechanisms of the disease are extremely complex, involving hypothalamic and trigeminovascular activation, cortical spreading depression, release of pro-inflammatory peptides, peripheral and central sensitization. The underlying cellular and molecular mechanisms have been scarcely investigated. Recently, genetic studies have suggested that different metabolic pathways could be involved in the pathogenesis of migraine.: This review focuses on cellular and molecular mechanisms involved in migraine, suggesting a role for circadian clocks, ion channels, synaptic plasticity, vascular factors, ion metal homeostasis, and impaired glucose metabolism in the pathogenesis of the disease. Accordingly, the article proposes new therapeutic targets that may be of particular relevance for disease prevention.: Several complex molecular mechanisms are involved in setting the genetic threshold for migraine and the pathogenesis of headache attacks. Most promising new therapeutic targets are the modulation of hypothalamic activity and ion channels involved in pain transmission. Further studies in animals and humans are necessary to enhance the elucidation of the molecular mechanisms of migraine and open new avenues for disease prevention.
Learn More >Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABARs and by an α1-to-α2GABAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAR-subtypes and restoring Cl homeostasis.
Learn More >Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis are long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer induced bone pain (CIBP). Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activate CB1 and CB2 receptors inhibiting inflammation and pain. We demonstrate that administration of MJN110 significantly and dose-dependently alleviates spontaneous pain behavior during acute administration compared to vehicle control. In addition, the MJN110 maintains its efficacy in a chronic dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose dependent and significant decrease in cell viability of 66.1 breast adenocarcinoma cells and to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden evidenced by radiograph or histological analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer induced bone pain. SIGNIFICANCE STATEMENT: Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non-opioid based therapies is essential and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone.
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