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Endogenous Pain Modulation (EPM) impairment is a significant contributor to chronic pain. Conditioned pain modulation (CPM) testing assesses EPM function. Osteoarthritic (OA) dogs are good translational models, but CPM has not been explored. Our aim was to assess EPM impairment in OA dogs compared to controls using CPM. We hypothesized that CPM testing would demonstrate EPM impairment in OA dogs compared to controls. Dogs with stifle/hip OA and demographically-matched controls were recruited. The pre-conditioning test stimulus, using mechanical/thermal quantitative sensory testing (MQST or TQST), were performed at the metatarsus. A 22N blunt probe (conditioning stimulus) was applied to the contralateral antebrachium for 2 minutes, followed by MQST or TQST (post-conditioning test stimulus). The threshold changes from pre to post-conditioning (∆MQST and ∆TQST) were compared between OA and control dogs. Twenty-four client-owned dogs (OA, n = 11; controls, n = 13) were recruited. The ∆MQST(p < 0.001) and ∆TQST(p < 0.001) increased in control dogs but not OA dogs (∆MQST p = 0.65; ∆TQST p = 0.76). Both ∆MQST(p < 0.001) and ∆TQST(p < 0.001) were different between the OA and control groups. These are the first data showing that EPM impairment is associated with canine OA pain. The spontaneous OA dog model may be used to test drugs that normalize EPM function.
Learn More >The legalization of cannabis in some states has intensified interest in the potential for cannabis and its constituents to lead to novel therapeutics for pain. Our understanding of the cellular mechanisms underlying cannabinoid actions in the brain have lagged behind opioids; however, the current opioid epidemic has also increased attention on the use of cannabinoids as alternatives to opioids for pain, especially chronic pain that requires long-term use. Endogenous cannabinoids are lipid signaling molecules that have complex roles in modulating neuronal function throughout the brain. In this review, we discuss cannabinoid functions in the descending pain modulatory pathway, a brain circuit that integrates cognitive and emotional processing of pain to modulate incoming sensory inputs. In addition, we highlight areas where further studies are necessary to understand cannabinoid regulation of descending pain modulation.
Learn More >Treating neuropathic pain is challenging and novel non-opioid based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence and in situ hybridization, we found the expression of the orphan GPCR (oGPCR) Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord (DH-SC) following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal (i.th.) CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element-binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights to its signaling pathways. CARTp is involved in many diseases including depression, reward and addiction, de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.
Learn More >Chronic inflammation increases the production of cytokines and activates pro-inflammatory pathways which may lead to non-specific low back pain (LBP). We systematically reviewed the literature to investigate whether inflammatory biomarkers are associated with non-specific LBP.
Learn More >The transient receptor potential (TRP) ion channel TRPM3 functions as a noxious heat sensor and plays a key role in acute pain sensation and inflammatory hyperalgesia in rodents. Despite its potential as novel analgesic drug target, little is known about the expression, function and modulation of TRPM3 in the human somatosensory system.
Learn More >Scientific progress requires transparency and openness. The ability to critique, replicate and implement scientific findings depends on the transparency of the study design and methods, and the open availability of study materials, data and code. Journals are key stakeholders in supporting transparency and openness. This study aimed to evaluate 10 highest ranked pain journals' authorship policies with respect to their support for transparent and open research practices. Two independent authors evaluated the journal policies (as at 27 May 2019) using three tools: the self-developed Transparency and Openness Evaluation Tool, the Centre for Open Science (COS) Transparency Factor and the International Committee of Medical Journal Editors (ICMJE) requirements for disclosure of conflicts of interest. We found that the journal policies had an overall low level of engagement with research transparency and openness standards. The median COS Transparency Factor score was 3.5 (IQR 2.8) of 29 possible points, and only 7 of 10 journals' stated requirements for disclosure of conflicts of interest aligned fully with the ICMJE recommendations. Improved transparency and openness of pain research has the potential to benefit all that are involved in generating and using research findings. Journal policies that endorse and facilitate transparent and open research practices will ultimately improve the evidence base that informs the care provided for people with pain.
Learn More >Irritable bowel syndrome (IBS) is a common functional disease characterized by chronic abdominal pain and changes in bowel movements. Effective therapy for visceral hypersensitivity in IBS patients remains challenging. This study investigated the roles of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB) and the effect of ANA-12 (a selective antagonist of TrkB) on chronic visceral hypersensitivity in an IBS-like rat model.
Learn More >The major symptoms of irritable bowel syndrome (IBS) are changes in bowel habits and abdominal pain. Psychological stress is the major pathophysiological components of IBS. Corticotropin-releasing factor (CRF) is a well-known integrator in response to psychological stress. In this study, a novel CRF1 receptor antagonist T-3047928 was evaluated in stress-induced IBS models of rats to explore its potency for IBS.
Learn More >Spinal cord injury (SCI) produces both locomotor deficits and sensory dysfunction that greatly reduce the overall quality of life. Mechanisms underlying chronic pain include increased neuro-inflammation and changes in spinal processing of sensory signals, with reduced inhibitory GABAergic signaling a likely key player. Our previous research demonstrated that spinal transplantation of GABAergic neural progenitor cells (NPCs) reduced neuropathic pain while intensive locomotor training (ILT) could reduce development of pain and partially reverse already established pain behaviors. Therefore, we evaluate the potential mutually beneficial anti-hypersensitivity effects of NPC transplants cells in combination with early or delayed ILT. NPC transplants were done at 4 weeks post-SCI. ILT, using a progressive ramping treadmill protocol, was initiated either 5 days post-SCI (early: pain prevention group) or at 5 weeks post-SCI (delayed: to reverse established pain) in male Sprague Dawley rats. Results showed that either ILT alone or NPCs alone could partially attenuate SCI neuropathic pain behaviors in both prevention and reversal paradigms. However, the combination of ILT with NPC transplants significantly enhanced neuropathic pain reduction on most of the outcome measures including tests for allodynia, hyperalgesia, and ongoing pain. Immunocytochemical and neurochemical analyses showed decreased pro-inflammatory markers and spinal pathology with individual treatments; these measures were further improved by the combination of either early or delayed ILT and GABAergic cellular transplantation. Lumbar dorsal horn GABAergic neuronal and process density were nearly restored to normal levels by the combination treatment. Together, these interventions may provide a less hostile and more supportive environment for promoting functional restoration in the spinal dorsal horn and attenuation of neuropathic pain following SCI. These findings suggest mutually beneficial effects of ILT and NPC transplants for reducing SCI neuropathic pain.
Learn More >Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with β-adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single-center, open-label, fixed-sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice-daily 80 mg propranolol under fasting conditions. Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was -6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing. Additionally, short-lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg) were observed following coadministration. Consistent with the largely nonoverlapping metabolic pathways of lasmiditan and propranolol, exposure to either drug was not affected by coadministration. Overall, compared with administration of either drug alone, coadministration was generally well tolerated.
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