Browse by Audience
High-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has a good level of evidence of efficacy as a method for providing analgesic effects in patients with chronic pain. However, there is still no consensus regarding the parameters of stimulation to use and the detailed protocol to apply for therapeutic practice. In this article, we review the main technical points to address, and we propose a practical algorithm of how to use rTMS for chronic pain treatment in daily clinical practice.
Learn More >Cortical spreading depolarization (CSD) is the electrophysiological substrate of migraine aura, and a putative trigger of trigeminovascular activation and migraine headache. Many migraineurs report stress or relief after a stress triggers an attack. We tested whether various stress conditions might modulate CSD susceptibility and whether this is dependent on genetic factors. Male and female wild type and familial hemiplegic migraine type1 (FHM1) knock-in mice heterozygous for the S218 L missense mutation were subjected to acute or chronic stress, or chronic stress followed by relief (36 h). Acute stress was induced by restraint and exposure to bright light and white noise (3 h). Chronic stress was induced for 28 days by two cycles of repeated exposure of mice to a rat (7d), physical restraint (3d), and forced swimming (3d). Electrical CSD threshold and KCl-induced (300 mM) CSD frequency were determined in occipital cortex in vivo at the end of each protocol. Relief after chronic stress reduced the electrical CSD threshold and increased the frequency of KCl-induced CSDs in FHM1 mutants only. Acute or chronic stress without relief did not affect CSD susceptibility in either strain. Stress status did not affect CSD propagation speed, duration or amplitude. In summary, relief after chronic stress, but not acute or chronic stress alone, augments CSD in genetically susceptible mice. Therefore, enhanced CSD susceptibility may explain why, in certain patients, migraine attacks typically occur during a period of stress relief such as weekends or holidays.
Learn More >To prospectively evaluate the abuse potential of NKTR-181, a novel opioid analgesic, in two phase 3 clinical trials using a newly developed reporting system: the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS®).
Learn More >We termed chronic neuropathic pain (NeP) in patients with diseases associated with spinal cord damage as "spinal cord-related pain syndrome". We conducted a survey of patients with the syndrome to assess the type and severity of NeP and its effect on QOL, and treatment modalities.
Learn More >In this study, we focused on several itch‑related molecules and receptors in the spinal cord with the goal of clarifying the specific mediators that regulate itch sensation. We investigated the involvement of serotonin receptors, opioid receptors, glia cell markers and chemokines (ligands and receptors) in models of acetone/ether/water (AEW)‑ and diphenylcyclopropenone (DCP)‑induced chronic itch. Using reverse transcription‑quantitative polymerase chain reaction, we examined the expression profiles of these mediators in the lower cervical spinal cord (C5‑8) of two models of chronic itch. We found that the gene expression levels of opioid receptor mu 1 (Oprm1), 5‑hydroxytryptamine receptor 1A (Htr1a) and 5‑hydroxytryptamine receptor 6 (Htr6) were upregulated. Among the chemokines, the expression levels of C‑C motif chemokine ligand (Ccl)21, Cxcl3 and Cxcl16 and their receptors, Ccr7, Cxcr2 and Cxcr6, were simultaneously upregulated in the spinal cords of the mice in both models of chronic itch. By contrast, the expression levels of Ccl2, Ccl3, Ccl4 and Ccl22 were downregulated. These findings indicate that multiple mediators, such as chemokines in the spinal cord, are altered and may be central candidates in further research into the mechanisms involved in the development of chronic itch.
Learn More >Inconsistent reporting of outcomes in clinical trials of treatments for Whiplash Associated Disorders (WAD) hinders effective data pooling and conclusions that can be drawn about the effectiveness of tested treatments. The aim of this study was to provide recommendations for core outcome domains that should be included in clinical trials of WAD.
Learn More >Pain is one of the most prevalent symptoms associated with cancer. Strong opioids are commonly used in the analgesic management of the disease, but carry the risk of severe side effects. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. For cancer patients, frequently experiencing multimorbidities and often exposed to polypharmacy, cebranopadol is easy to handle given its once-daily dosing, the small tablet size that enables swallowing, and the option to flexibly titrate to an effective dose.
Learn More >Emerging evidence implicates the upregulation of matrix metalloproteinase (MMP)-9/2 in the dorsal root ganglion (DRG) and spinal cord as a contributor to the pathogenesis of chronic pain. In the current study, the expression of MMP-9/2 in wounded tissue, ipsilateral DRG, and the spinal dorsal horn as well as its role in the development of postoperative pain were examined following plantar incision in rats. Our results showed that plantar incision resulted in increased expression of MMP-9/2 in wounded tissue and ipsilateral L4/5 DRGs. Although gelatin zymography detected an increased activity of MMP-9, only MMP-2 protein was increased in the spinal cord. Results of double immunofluorescence staining showed MMP-2 expression in DRG neurons and satellite glial cells, but MMP-9 was found only in neurons. In the spinal cord, MMP-2 was expressed in neurons and astrocytes, and MMP-9 was expressed in neurons and somewhat in microglial cells. Planter incision also elicited increased expression of p-Erk, p-p38, and IL-1β in wounded tissue, ipsilateral L4/5 DRGs, and dorsal horn. Prior intraplantar or intrathecal injection of MMP-9- and MMP-2-specific inhibitors partially prevented reductions of paw withdrawal threshold and paw withdrawal latency following plantar incision. The maturation of IL-1β was also inhibited by the treatment. Moreover, MMP-9 inhibition suppressed p38, and MMP-2 inhibitor reduced the Erk phosphorylation in wounded tissue, DRGs, and dorsal horn. Immunofluorescence staining detected colocalization of MMP-9 with p38 and MMP-2 with Erk in DRG and spinal cord. Together, the above results reveal that upregulated MMP-9 via p38/IL-1β and MMP-2 via Erk/IL-1β signaling in the wounded tissue, ipsilateral DRG, and dorsal horn contribute to the development of postoperative pain.
Learn More >Chronic neuropathic pain is a burden to millions of patients every day. Patients with neuropathic pain will also experience acute pain throughout their everyday lives adding to their nociceptive burden. Using nociceptive models in mice this study aimed to investigate the relationship between acute visceral pain and chronic neuropathic pain in spontaneous and affective behaviors. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve of C57BL/6J male mice and examined in assays of acetic acid (AA)-induced stretching or conditioned place aversion to assess nociceptive and aversive behaviors. Stretching induced by a low concentration (0.32%) of AA given intraperitoneally was significantly increased in CCI and paclitaxel-treated animals compared to control animals. A higher concentration (1.2%) of AA was able to induce stretching equally in both neuropathic and control mice. In the conditioned place aversion test, an AA concentration of 0.32% did not induce place aversion in either sham or CCI animals. However, the 1.2% concentration of AA-induced higher place aversion scores in CCI mice compared to sham mice. No difference in place conditioning was observed between paclitaxel and vehicle-treated mice. Overall, our results show that peripheral nerve injury and paclitaxel treatment induces hypersensitivity to AA-induced nociception and place aversion.
Learn More >Accumulating evidence demonstrates the beneficial effects of physical exercise on pain conditions; however, the underlying mechanisms are not understood thoroughly. The purpose of the present study was to investigate the effects of regular swimming exercise on neuroma pain and the possible roles of adipokines (leptin and adiponectin) in the pain behaviors modulated by exercise. The results showed that 5 weeks of regular swimming exercise relieved pain behaviors in a rat model of neuroma pain and normalized the dysregulation of circulating leptin and adiponectin in plasma induced by nerve injury. Moreover, regular swimming exercise reversed the altered expressions of leptin receptor and adiponectin receptor 1 in neuroma. In addition, the administration of exogenous leptin to the neuroma site dampened the effects of regular swimming exercise on neuroma pain and adiponectin administration alleviated the neuroma pain in the non-exercised neuroma rats. These findings indicate that leptin and adiponectin might be involved in mediating the beneficial effects of exercise on neuroma pain. PERSPECTIVE: Perspective: Identifying which endogenous processes are activated by specific exercise regimes would likely reveal novel therapeutic targets for the treatment of neuropathic pain. The current study suggests that adipokines might be involved in pain behaviors modulated by exercise and thus presents them as potential targets for pain management.
Learn More >