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Non-selective glutamate AMPA receptor antagonists are efficacious in chronic pain, but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in CNS. Recently, LY3130481 has been shown to selectively block AMPA receptors co-assembled with the auxiliary protein, TARP γ8, which is highly expressed in hippocampus, but also in pain pathways, including anterior cingulate (ACC) and somatosensory (SS) cortices and spinal cord, suggesting that selective blockade γ8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant γ8-containing AMPA receptors was modulated by co-expression with other TARPs; γ2 subunits affected activity more than γ3 subunits. Consistent with these findings, LY3130481 had decreasing potency on receptors from rat hippocampal, cortical, spinal cord, and cerebellar neurons that was replicated in tissue from human brain. LY3130481 partially suppressed, whereas the non-selective AMPA antagonist GYKI53784 completely blocked AMPA receptor-dependent EPSPs in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response stimulation of peripheral afferents. LY3130481 also significantly reduced nocifensive behaviors after intraplantar formalin that was correlated with occupancy of CNS γ8-containing AMPA receptors. In addition, LY3130481 dose-dependently attenuated established gait impairment after joint damage and tactile allodynia after spinal nerve ligation; all in the absence of motor side effects. Collectively, these data demonstrate that LY3130481 can suppress excitatory synaptic transmission and plasticity in pain pathways containing γ8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective and safer therapy for chronic pain conditions.
Learn More >To understand the process of change at an individual level, this study used a single-case experimental design to evaluate how change in potential mediators related to change in disability over time, during an exposure-based behavioural intervention in four people with chronic low back pain and high pain-related fear. A second aim was to evaluate whether the change (sequential or simultaneous) in mediators and disability occurred at the same timepoint for all individuals.
Learn More >Transmembrane member 16A (TMEM16A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contraction, and may be important in peripheral pain transmission. To explore the role of TMEM16A in the persistent hyperalgesia that results from chronic constriction injury-induced neuropathic pain, a rat model of the condition was established by ligating the left sciatic nerve. A TMEM16A selective antagonist (10 μg T16Ainh-A01) was intrathecally injected at L5-6. For measurement of thermal hyperalgesia, the drug was administered once at 14 days and thermal withdrawal latency was recorded with an analgesia meter. For measurement of other indexes, the drug was administered at 12 days, once every 6 hours, totally five times. The measurements were performed at 14 days. Western blot assay was conducted to analyze TMEM16A expression in the L4-6 dorsal root ganglion. Immunofluorescence staining was used to detect the immunoreactivity of TMEM16A in the L4-6 dorsal root ganglion on the injured side. Patch clamp was used to detect electrophysiological changes in the neurons in the L4-6 dorsal root ganglion. Our results demonstrated that thermal withdrawal latency was shortened in the model rats compared with control rats. Additionally, TMEM16A expression and the number of TMEM16A positive cells in the L4-6 dorsal root ganglion were higher in the model rats, which induced excitation of the neurons in the L4-6 dorsal root ganglion. These findings were inhibited by T16Ainh-A01 and confirm that TMEM16A plays a key role in persistent chronic constriction injury-induced hyperalgesia. Thus, inhibiting TMEM16A might be a novel pharmacological intervention for neuropathic pain. All experimental protocols were approved by the Animal Ethics Committee at the First Affiliated Hospital of Shihezi University School of Medicine, China (approval No. A2017-170-01) on February 27, 2017.
Learn More >The chronic pain syndrome inherited erythromelalgia (IEM) is attributed to mutations in the voltage-gated sodium channel (Nav) 1.7. Still, recent studies targeting Nav1.7 in clinical trials have provided conflicting results. Here, we differentiated induced pluripotent stem cells (iPS cells) from IEM patients with the Nav1.7/I848T mutation into sensory nociceptors. Action potentials in these IEM nociceptors displayed a decreased firing threshold, an enhanced upstroke and afterhyperpolarization, all of which may explain the increased pain experienced by patients. Subsequently, we investigated the voltage dependence of the tetrodotoxin-sensitive Nav activation in these human sensory neurons using a specific pre-pulse voltage protocol. The IEM mutation induced a hyperpolarizing shift of Nav activation which leads to activation of Nav1.7 at more negative potentials. Our results indicate that Nav1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes significantly to the action potential upstroke. Thus, our model system with iPS cell-derived sensory neurons provides a new rationale for Nav1.7 function and promises to be valuable as a translational tool to profile and develop more efficacious clinical analgesics.
Learn More >No consensus exists for defining chronic preoperative opioid use. Most spine studies rely solely on opioid duration to stratify patients into preoperative risk categories.
Learn More >Postoperative pain is common and promotes opioid use. Surgical wounds are hypoxic because normal perfusion is impaired. Local wound ischemia and acidosis promote incisional pain. Some evidence suggests that improving oxygen supply to surgical wounds might reduce pain. We therefore tested the hypothesis that supplemental (80% inspired) intraoperative oxygen reduces postoperative pain and opioid consumption.
Learn More >Multiple studies have evaluated the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and migraine risk with conflicting results. Therefore, we conducted a meta-analysis on this theme.
Learn More >Understanding the molecular biology of opioid analgesia is essential for its proper implementation and mechanistic approach to its modulation in order to maximize analgesia and minimize undesired effects. By appreciating the molecular mechanisms intrinsic to opioid analgesia, one can manipulate a molecular target to augment or diminish a specific effect using adjuvant drugs, select an appropriate opioid for opioid rotation or define a molecular target for new opioid drug development. In this review, we present the cellular and molecular mechanisms of opioid analgesia and that of the associated phenomena of tolerance, dependence, and hyperalgesia. The specific mechanisms highlighted are those that presently can be clinically addressed.
Learn More >To review 5 new areas in primary headache disorders, especially migraine and cluster headache.
Learn More >Autophagy is a lysosomal degradation pathway that maintains tissue homeostasis by recycling damaged and aged cellular components, which plays important roles in development of the nervous system, as well as in neuronal function and survival. In addition, autophagy dysfunction underlies neuropathic pain. Thus, the modulation of autophagy can alleviate neuropathic pain. Here, we describe the definition, mechanisms of autophagy and neuropathic pain. On this basis, we further discuss the role of autophagy dysfunction in neuropathic pain. This review updates our knowledge on autophagy mechanisms which propose potential therapeutic targets for the treatment of neuropathic pain.
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