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Neuroimaging studies have shown that chronic pain is maladaptive and influences brain function and behavior by altering the flexible cerebral information flow. We utilized power spectral analysis to investigate the impact of classic trigeminal neuralgia (TN) on the oscillation dynamics of intrinsic brain activity in humans. The amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) were measured in 29 TN patients and 34 age- and sex-matched healthy controls (HCs) via resting-state functional MRI (R-fMRI). Two different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz) were analyzed. Differences in blood oxygen level-dependent (BOLD) signal fluctuations and related resting-state functional connectivity (rsFC) between the TN patients and HCs were identified. The TN patients had reduced ALFF/fALFF in the posterior cingulate cortex (PCC), left insula, left dorsolateral prefrontal cortex (DLPFC), left putamen and bilateral temporal lobe, exclusively in the frequency of the slow-5 band. Whole brain rsFC analyses with these six different regions as seeds revealed two weaker circuits including the PCC-medial prefrontal cortex (mPFC) and DLPFC-hippocampus circuits, indicating abnormal interactions with the default mode network (DMN) in TN patients. The functional connectivity between the default-mode regions (mPFC and PCC) in the slow-5 band tracked pain intensity. Together, our results provide novel insights into how TN disturbs the cortical rhythms and functional interactions of the brain. These insights may have implications for the understanding and treatment of brain dysfunction in chronic pain patients, including TN patients.
Learn More >Amongst the regulators of voltage-gated ion channels is the collapsin response mediator protein 2 (CRMP2). CRMP2 regulation of the activity and trafficking of NaV1.7 voltage-gated sodium channels as well as the N-type (CaV2.2) voltage-gated calcium channel (VGCC) has been reported. On the other hand, CRMP2 does not appear to regulate L- (CaV1.x), P/Q- (CaV2.1), and R- (CaV2.3) type high VGCCs. Whether CRMP2 regulates low VGCCs remains an open question. Here, we asked if CRMP2 could regulate the low voltage-gated (T-type/CaV3.x) channels in sensory neurons. Reducing CRMP2 protein levels with short interfering RNAs yielded no change in macroscopic currents carried by T-type channels. No change in biophysical properties of the T-type currents was noted. Future studies pursuing CRMP2 druggability in neuropathic pain will benefit from the findings that CRMP2 regulates only the N-type (CaV2.2) calcium channels.
Learn More >Alcohol use and chronic pain are highly comorbid. Acute alcohol use typically produces an analgesic effect. However, chronic use can worsen the progression of chronic pain. In rodent models, acute models of pain have primarily been used to investigate the relationship between alcohol and pain analgesia. Here, we use two models of chronic pain, chronic inflammatory and peripheral neuropathic pain, to investigate acute alcohol's antinociceptive and analgesic properties. We hypothesize that acute ethanol is acting through opioid receptors to create an analgesic-like effect in both reflexive and affective dimensions of pain. Using male and female C57BL/6J mice, oral ethanol administration (0-1.25 g/kg) showed a dose-dependent reversal of mechanical hypersensitivity in both Complete Freund's Adjuvant (CFA) and chronic constriction injury (CCI) models of chronic inflammatory and neuropathic pain. No sex differences were observed. Using the conditioned place preference (CPP) task to assess the subjective responses to ethanol's anti-nociceptive properties, CCI-injured animals showed a preference for the ethanol-paired side, suggesting a reduction in an aversive and pain-like state produced by nerve injury. These effects are likely mediated through the kappa and possibly the mu opioid systems, since ethanol-induced anti-nociception following CCI was fully reversed by pretreatment with the kappa selective antagonist, nor-BNI, or high doses of naltrexone. These data show that ethanol possesses analgesic-like properties in chronic inflammatory and neuropathic pain models in mice and provide new insight into ethanol as it relates to chronic pain.
Learn More >Prostaglandin E2 (PGE2) and proton are typical inflammatory mediators. They play a major role in pain processing and hypersensitivity through activating their cognate receptors expressed in terminals of nociceptive sensory neurons. However, it remains unclear whether there is an interaction between PGE2 receptors and proton-activated acid-sensing ion channels (ASICs). Herein, we show that PGE2 enhanced the functional activity of ASICs in rat dorsal root ganglion (DRG) neurons through EP1 and EP4 receptors. In the present study, PGE2 concentration-dependently increased ASIC currents in DRG neurons. It shifted the proton concentration-response curve upwards, without change in the apparent affinity of proton for ASICs. Moreover, PGE2 enhancement of ASIC currents was partially blocked by EP1 or EP4 receptor antagonist. PGE2 failed to enhance ASIC currents when simultaneous blockade of both EP1 and EP4 receptors. PGE2 enhancement was partially suppressed after inhibition of intracellular PKC or PKA signaling, and completely disappeared after concurrent blockade of both PKC and PKA signaling. PGE2 increased significantly the expression levels of p-PKCε and p-PKA in DRG cells. PGE2 also enhanced proton-evoked action potentials in rat DRG neurons. Finally, peripherally administration of PGE2 dose-dependently exacerbated acid-induced nocifensive behaviors in rats through EP1 and EP4 receptors. Our results indicate that PGE2 enhanced the electrophysiological activity of ASICs in DRG neurons and contributed to acidosis-evoked pain, which revealed a novel peripheral mechanism underlying PGE2 involvement in hyperalgesia by sensitizing ASICs in primary sensory neurons.
Learn More >Chronic pruritus is a relevant symptom burden in various systemic diseases. It is most commonly observed in patients with chronic kidney disease, hepatobiliary and hematological disorders as well as adverse drug reaction. Recent basic research has unraveled novel treatment targets which are currently in pre-clinical phases, clinical trials or have already been licensed. While μ-opioid receptor antagonists have been used since decades mainly in cholestatic pruritus, the k-opioid receptor agonist nalfurafine has been licensed in Japan for chronic kidney disease associated pruritus (CKDaP) as well as cholestatic pruritus. Further κ-opioid receptor agonists are currently investigated in various clinical trials including CKDaP. In recent years, the calcium channel blockers gabapentin and pregabalin have also been recognized as effective anti-pruritus therapy in several internal diseases with the best evidence in chronic kidney disease associated pruritus. Neurokinin-1 receptor antagonists have been investigated with variable benefit in CKDaP, solid tumors and lymphoproliferative disorders such as cutaneous T-cell lymphoma, Sézary syndrome. Inhibitors of the ileal bile acid transporter (IBAT) represent a selective interruption of the enterohepatic circulation and are currently investigated in various hepatobiliary disorders associated with pruritus. The current development and testing of novel drugs in clinical trials offers hope to struggling physicians and suffering patients. This article is protected by copyright. All rights reserved.
Learn More >Preemptive Analgesia With Oxycodone Is Associated With More Pain Following Total Joint Arthroplasty.
Preemptive multimodal analgesia (PMA) is a commonly used technique to control pain following total joint arthroplasty. PMA protocols use multiple analgesics immediately preoperatively to prevent central sensitization and amplification of pain during surgery. While benefits of some individual components of a PMA protocol have been established, there are little data to support inclusion or exclusion of opioids in this context.
Learn More >Chronic pain occurs in 83% of Parkinson disease (PD) patients and deep brain stimulation (DBS) has shown to result in pain relief in a subset of patients, though the mechanism is unclear.
Learn More >Chronic pain is common in patients with prescription opioid use disorder (OUD), and pain severity has been shown to predict opioid use for those with chronic pain. However, recent research suggests that focusing on pain status (i.e., the presence or absence of chronic pain) at treatment initiation may not reflect the clinical significance of pain over the long-term course of OUD. Reports of variability in chronic pain and its clinical significance over time have yet to be investigated in patients with prescription OUD. The present study examined variability in chronic pain status from entry into prescription OUD treatment through 3.5-year follow-up. Additionally, we examined the association between concurrent chronic pain and opioid use at three follow-up time points.
Learn More >The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.
Learn More >Current Evidence on Potential Uses of MicroRNA Biomarkers for Migraine: From Diagnosis to Treatment.
Migraine is a disabling and recurrent neurological disorder characterized by headache attacks that are often accompanied by sensory and motor disturbances. The value and importance of reliable biomarkers in migraine have been long recognized and a diverse range of biomarkers from biological samples to electrophysiological patterns and brain imaging has been proposed. There is still no consensus on specific biomarker(s) for migraine. Ideally, not a single but a battery of biomarkers would provide a multidisciplinary way to understand and treat migraine better. Translational research has witnessed an escalating number of studies on microRNAs (miRNAs) during the last decade. Identification of the first miRNA occurred in 1993, and currently more than 2000 human miRNAs have been recognized. miRNAs are a group of endogenous small non-coding molecules that play a key role in post-transcriptional gene processes and hence are involved in health and disease. miRNAs have already been found to be involved in the onset and progression of several human disorders including chronic pain conditions; however, there have been far fewer studies in migraine and other headaches. Current evidence does suggest that miRNAs play a role in migraine and its relief and hence these molecules are proposed as potential migraine biomarkers. This review updates the current evidence for the role of miRNAs in migraine; including their potential as biomarkers, with a role in understanding of its pathogenesis, the population at risk, diagnosis, patient stratification, chronification risk factors, response to treatments, and miRNA-based therapeutic options. Limitations exist and further research is required to completely unwrap the potential of miRNAs in migraine research and practice.
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