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Neuroinflammation is a major component in the transition to and perpetuation of neuropathic pain states. Spinal neuroinflammation involves activation of TLR4, localized to enlarged, cholesterol-enriched lipid rafts, designated here as inflammarafts. Conditional deletion of cholesterol transporters ABCA1 and ABCG1 in microglia, leading to inflammaraft formation, induced tactile allodynia in naive mice. The apoA-I binding protein (AIBP) facilitated cholesterol depletion from inflammarafts and reversed neuropathic pain in a model of chemotherapy-induced peripheral neuropathy (CIPN) in wild-type mice, but AIBP failed to reverse allodynia in mice with ABCA1/ABCG1-deficient microglia, suggesting a cholesterol-dependent mechanism. An AIBP mutant lacking the TLR4-binding domain did not bind microglia or reverse CIPN allodynia. The long-lasting therapeutic effect of a single AIBP dose in CIPN was associated with anti-inflammatory and cholesterol metabolism reprogramming and reduced accumulation of lipid droplets in microglia. These results suggest a cholesterol-driven mechanism of regulation of neuropathic pain by controlling the TLR4 inflammarafts and gene expression program in microglia and blocking the perpetuation of neuroinflammation.
Learn More >Chronic pain is a complex disease that affects a large proportion of the population. With little to no effective treatments currently available for patients, this malady presents a large burden to society. has been previously used to describe conserved molecular components of nociception in larvae and adults. However, adult assays tend to rely on avoidance behaviours, and whilst larval acute thermal avoidance assays exist, larvae are not best suited to a chronic pain scenario as the condition must be long-term. Therefore, an adult thermal nociception response assay was required to study injury-evoked changes in heat nociception threshold (allodynia and hyperalgesia) over time, and we describe such a protocol here. Following leg amputation, flies display increased thermal sensitivity (allodynia) to innocuous temperatures but not an increase in magnitude of response (hyperalgesia) to noxious heat. Our method allows for individualised analysis of both allodynia and hyperalgesia.
Learn More >Lysophosphatidic acid (LPA) plays a critical role in developing and maintaining chronic pain in various animal models. Previous studies have reported that cytosolic and calcium-independent phospholipase A (PLA) is involved in the LPA receptor-mediated amplification of LPA production in the spinal dorsal horn (SDH) after nerve injury, while the involvement of secreted PLA (sPLA) remains unclear. The present study revealed that only sPLA -III among 11 species of PLA showed a significant upregulation of gene expression in the SDH. Intraspinal injection of adeno-associated virus-miRNA targeting sPLA-III prevented hyperalgesia and unique hypoalgesia in mice treated with partial sciatic nerve ligation. In addition, intrathecal treatment with antisense oligodeoxynucleotide or siRNA targeting sPLA-III significantly reversed the established thermal hyperalgesia. In the high-throughput screening of sPLA-III inhibitors from the chemical library, we identified two hit compounds. Through in vitro characterization of PLA inhibitor profiles and in vivo assessment of the anti-hyperalgesic effects of known PLA inhibitors as well as hit compounds, sPLA-III was found to be a novel therapeutic target molecule for the treatment of Neuropathic pain.
Learn More >Stress contributes to major depressive disorder (MDD) and chronic pain, which affect a significant portion of the global population, but researchers have not clearly determined how these conditions are initiated or amplified by stress. The chronic social defeat stress (CSDS) model is a mouse model of psychosocial stress that exhibits depressive-like behavior and chronic pain. We hypothesized that metabotropic glutamate receptor 5 (mGluR5) expressed in the nucleus accumbens (NAc) normalizes the depressive-like behaviors and pain following CSDS. Here, we show that CSDS induced both pain and social avoidance and that the level of mGluR5 decreased in susceptible mice. Overexpression of mGluR5 in the NAc shell and core prevented the development of depressive-like behaviors and pain in susceptible mice, respectively. Conversely, depression-like behaviors and pain were exacerbated in mice with mGluR5 knockdown in the NAc shell and core, respectively, compared to control mice subjected to 3 days of social defeat stress. Furthermore, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, reversed the reduction in the level of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the NAc of susceptible mice, an effect that was blocked by 3-((2-methyl-1, 3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP), an mGluR5 antagonist. In addition, the injection of CHPG into the NAc shell and core normalized depressive-like behaviors and pain, respectively, and these effects were inhibited by AM251, a cannabinoid type 1 receptor (CB1R) antagonist. Based on these results, mGluR5-mediated eCB production in the NAc relieves stress-induced depressive-like behaviors and pain.
Learn More >Pain is a universal experience and the most common reason for seeking healthcare. Inadequate pain management negatively impacts numerous aspects of patient health. Multidisciplinary treatment programmes, including psychosocial interventions, are more useful for pain management than purely biomedical treatment alone. Recently, researchers showed increasing interest in understanding the role of spirituality/religiosity and spiritual/religious practices on pain experience, with engagement in religious practices, such as prayer, showing to positively impact pain experience in religious individuals. This systematic review will seek to summarise and integrate the existing findings from randomised controlled trials assessing the effects of prayer and prayer-based interventions on pain experience.
Learn More >The study aimed to assess the feasibility of recording electrically evoked compound action potentials (ECAPs) from the rat spinal cord. To achieve this, we characterized electrophysiological responses of dorsal column (DC) axons from electrical stimulation and quantified the relationship between ECAP and motor thresholds (ECAPTs and MTs).
Learn More >To determine whether erenumab is effective and safe in refractory chronic migraine with medication overuse headache.
Learn More >The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys and Trp to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (K 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t > 24 h) compared with NT (t ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED = 4.6 µg/kg) and tonic (ED = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
Learn More >Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, two-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and three sets of assessments were done at each of the two visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing (QST), spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test – hand in 2° water for two minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive QST measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia. Perspective: This exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.
Learn More >Patient Reported Outcomes (PROs) are utilized in clinical registries and trials, necessitating development of benchmarks to enhance interpretability. This study aimed to 1) examine if PROMIS measures administered via computer adaptive testing (CAT) were responsive to change, and 2) highlight one method of assessing clinically significant change for youth seen in a tertiary pain clinic. Clinically significant change was achieved if patients had significantly reliable pre-to-post-changes greater than Reliable Change Index (RCI) value and reported decreased symptoms by at least one severity level (e.g., moderate to mild). Participants were 328 youth (8-17 years old) seen in a tertiary pediatric pain management clinic. Small to moderate effect sizes were noted across PROMIS measures (except Peer Relations). Reliable magnitudes of change were estimated for this sample as approximately 6-point reduction for Pain Interference and Mobility, 9 for Fatigue, and 11 for Anxiety and Depression. Depending on the measure, 10-24% were categorized as improved, 3-6% as deteriorated, and 68-81% were either not clinically elevated at baseline or remained unchanged at 3-months. Overall, PROMIS CAT measures demonstrated responsiveness to change over time. Estimation of clinically significant change offers preliminary yet rigorous benchmarks for evaluating treatment response and sets the stage for understanding treatment effects. Perspective This study assesses responsiveness of CAT administered PROMIS measures and highlights one methodological approach of presenting clinical significance for assessing treatment outcomes in pediatric chronic pain. These benchmarks will allow clinicians and researchers to evaluate treatment response utilizing PROs while allowing for a deeper understanding of treatment effects.
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