Papers: 20 Aug 2022 - 26 Aug 2022

The loss of GABAergic inhibition is a mechanism that underlies neuropathic pain. Therefore, rescuing the GABAergic inhibitory tone through activation of GABAA receptors is a strategy to reduce neuropathic pain. This study was designed to elucidate the function of the spinal α6-containing GABAA receptor in physiological conditions and neuropathic pain in female and male rats. Results show that α6-containing GABAA receptor blockade or transient α6-containing GABAA receptor knockdown induces evoked hypersensitivity and spontaneous pain in naïve female rats. The α6 subunit is expressed in IB4+ and CGRP+ primary afferent neurons in the rat spinal dorsal horn and dorsal root ganglia (DRG), but not astrocytes. Nerve injury reduces α6 subunit protein expression in the central terminals of the primary afferent neurons and DRG, whereas intrathecal administration of positive allosteric modulators (PAMs) of the α6-containing GABAA receptor reduces tactile allodynia and spontaneous nociceptive behaviors in female, but not male, neuropathic rats and mice. Overexpression of the spinal α6 subunit reduces tactile allodynia and restores α6 subunit expression in neuropathic rats. PAMs of the α6-containing GABAA receptor induces a greater antiallodynic effect in females compared to male rats and mice. Finally, α6 subunit is expressed in humans. This receptor is found in CGRP+ and P2X3+ primary afferent fibers but not astrocytes in the human spinal dorsal horn. Our results suggest that the spinal α6-containing GABAA receptor has a sex-specific antinociceptive role in neuropathic pain, suggesting that this receptor may represent an interesting target to develop a novel treatment for neuropathic pain.

Nociception and motor coordination are critically governed by glycine receptor (GlyR) function at inhibitory synapses. Consequentially, GlyRs are attractive targets in the management of chronic pain and in the treatment of several neurological disorders. High-resolution mechanistic details of GlyR function and its modulation are just emerging. While it has been known that cannabinoids such as Δ-tetrahydrocannabinol (THC), the principal psychoactive constituent in marijuana, potentiate GlyR in the therapeutically relevant concentration range, the molecular mechanism underlying this effect is still not understood. Here, we present Cryo-EM structures of full-length GlyR reconstituted into lipid nanodisc in complex with THC under varying concentrations of glycine. The GlyR-THC complexes are captured in multiple conformational states that reveal the basis for THC-mediated potentiation, manifested as different extents of opening at the level of the channel pore. Taken together, these structural findings, combined with molecular dynamics simulations and functional analysis, provide insights into the potential THC binding site and the allosteric coupling to the channel pore.

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

In response to the overuse of prescription opioid analgesics, clinical practice guidelines encourage opioid deprescribing (i.e. dose reduction or cessation) in patients with chronic non-cancer pain. Therefore, this study evaluated and compared international clinical guideline recommendations on opioid deprescribing in patients with chronic non-cancer pain.We searched PubMed, EMBASE, PEDro, National Institute for Health and Care Excellence (United Kingdom) and MAGICapp databases from inception to 4th June 2021, with no language or publication restrictions. Additionally, we searched The National Guideline Clearinghouse and International Guideline Network database from inception to December 2018. Two independent reviewers conducted the initial title and abstract screening. After discrepancies were resolved via discussion, two independent reviewers conducted the full-text screening of each potentially eligible reference. Four independent reviewers completed the pre-piloted, standardized data extraction forms of each included guideline. Extracted information included; bibliographical details, strength of recommendations and the outcomes; when and how to deprescribe, managing withdrawal symptoms, additional support, outcome monitoring and deprescribing in co-prescription of sedatives. A narrative synthesis was used to present the results.This study found that clinical practice guidelines agree on when and how to deprescribe opioid analgesics, but lack advice on managing a patient's withdrawal symptoms, outcome monitoring and deprescribing with co-prescription of sedatives. Quality assessment of the guidelines suggests that greater discussion on implementation and dissemination is needed.

Melatonin, through its G protein-coupled MT receptor, is implicated in analgesia, but the relationship between MT receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured, SNI), the selective melatonin MT agonist UCM924 reversed the allodynia (a pain response to a non-noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the non-selective opioid antagonist naloxone and the selective MOR antagonist CTOP blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral-ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pro-nociceptive ON-cells, and the enhancement of the firing of the anti-nociceptive OFF-cells, induced by the microinjection of the MT agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT receptors are expressed in both excitatory (CaMKIIα ) and inhibitory (GAD65 ) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons co-expressed MOR and MT receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT receptor agonism requires MORs to exert its antiallodynic effects, mostly through an inter-neuronal circuit involving MOR and MT receptors. This article is protected by copyright. All rights reserved.

Persistent pain despite satisfactory disease treatment is frequent in rheumatoid arthritis (RA) and spondyloarthritis (Spa) and may result from specific changes in central pain processing. We assessed these mechanisms further, by systematically comparing thermal pain thresholds and conditioned pain modulation (CPM) between patients with active RA or Spa and healthy controls.We included 50 RA and 50 Spa patients and 100 age- and sex-matched controls. Heat and cold pain thresholds (HPT-CPT) were measured on the dominant forearm, and CPM was assessed by applying conditioning stimuli (immersion in a cold water bath) to one foot and the non-dominant hand in two successive randomized sequences. Descending pain modulation was assessed as the difference in HPT (in °C) before and after conditioning. Larger HPT differences (i.e. a larger CPM effect) reflected more efficient descending inhibition. Potential associations between changes in CPM and clinical data, including disease activity, pain intensity, psychological and functional variables, were systematically assessed.HPT and CPT were similar in patients and controls. Mean CPM effect was significantly weaker in patients than controls for conditioning applied to either the foot (0.25°C ±2.57 vs. 2.79°C ±2.31; p<0.001) or the non-dominant hand (0.57°C ±2.74 vs. 2.68°C ±2.12; p<0.001).The smaller CPM effect in patients was correlated with average pain intensity, but not with disease activity or other clinical characteristics, suggesting a significant pathophysiological role for changes in endogenous pain modulation in the mechanisms of chronic pain associated with inflammatory rheumatism.

The exact mechanism and site of action of triptans in aborting migraine attacks remain under debate. We hypothesized that the clinical efficacy of triptans lies in aborting central sensitization and focused on the question of why triptans are headache-specific, i.e. highly effective in migraine and cluster headache and ineffective in extracephalic pain.

We sought to identify and characterize distinct responder profiles among osteoarthritis (OA) subjects treated with tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), or placebo.

The prevalence of osteoarthritis (OA) is rising, and pain is the hallmark symptom of OA. Pain in OA is complicated and can be influenced by multiple joint-related factors and factors related to, e.g., physiological, epigenetic, and pain sensory profiles. Increasing evidence suggests that a subset of patients with OA are pain sensitive. This can be assessed using quantitative sensory testing (QST). Common treatments of OA are total knee arthroplasty (TKA) and administration of 3-weeks of non-steroidal anti-inflammatory drugs (NSAIDs), which provide pain relief to many patients with OA. However, approx. 20% of patients experience chronic postoperative pain after TKA, whereas NSAIDs provide an average pain relief of approx. 25%. The current topical review focuses on the emerging evidence linking pretreatment QST to the treatment response of TKA and NSAID treatments.

Translation of promising preclinical efficacy data for investigational analgesics to positive clinical trial outcomes is limited, despite the large collective effort to date. However, one target with positive proof-of-concept clinical trial data is the angiotensin II type 2 (AT2) receptor. This review addresses the obstacles impeding successful preclinical to clinical research translation in the novel analgesics field, and it also provides an overview of the discovery and development of EMA401, a peripherally restricted, highly selective, orally active, small-molecule AT2 receptor antagonist for relief of neuropathic pain. Multiple AT2 receptor antagonists evoked dose-dependent antiallodynia in the chronic constriction injury of the sciatic nerve rat model of neuropathic pain. In AT2 receptor knockout chronic constriction injury mice, antiallodynia was abolished, affirming the AT2 receptor as the target. Subsequently, AT2 receptor antagonists were shown to evoke pain relief in multiple rodent chronic pain models. EMA401 (sodium salt) was selected as the drug candidate based on its >10,000-fold binding selectivity c.f. the angiotensin II type 1 receptor, good potency, and favourable pharmacokinetics. Animal toxicology and safety testing along with phase 1 clinical trials in healthy volunteers showed that oral EMA401 was safe and well-tolerated. Based on these data, a proof-of-concept clinical trial of oral EMA401 was undertaken in patients with postherpetic neuralgia. This 4-week trial showed that EMA401 evoked superior relief of postherpetic neuralgia relative to placebo and there were no serious adverse events in the EMA401 group.

TRPC5 belongs to the mammalian superfamily of transient receptor potential (TRP) Ca-permeable cationic channels and it has been implicated in various CNS disorders. As part of our ongoing interest in the development of a PET radiotracer for imaging TRPC5, herein, we explored the radiosynthesis, and in vitro and in vivo evaluation of a new C-11 radiotracer [C]HC070 in rodents and nonhuman primates.

In the past, systematic reviews (SRs) and meta-analyses (MAs) have been used to assess the efficacy of Chinese herbal medicine (CHM) in the treatment of migraines. However, robust conclusions have not yet been determined because of variations in the methodological and evidence quality of these SRs/MAs. We aimed to assess the methodological and reporting quality of SRs/MAs and evaluate the available evidence of the efficacy of CHM treatment of migraines. We searched eight electronic databases from inception until 10 January 2022, without language restrictions. Two researchers were independently responsible for study screening and data extraction. The methodological and reporting quality of SRs/MAs were assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The evidence quality of included SRs/MAs was evaluated by Grading of Recommendations Assessment, Development and Evaluation (GRADE). In addition, a descriptive analysis of the included SRs/MAs was included. Sixteen SRs/MAs, including 69 outcomes, were finally included in this overview. Data synthesis of the included SRs/MAs outcomes showed that CHM plus Western medicine (WM) was beneficial in the improvement of migraines. In comparison, there was conflicting evidence for the effectiveness of CHM used alone. CHM was better than WM in improving responder rate and acute medication usage and was superior to placebo in improving migraine days, responder rate, and migraine duration. However, there was insufficient evidence to verify the effectiveness of CHM for migraine treatment regarding pain severity and migraine frequency. All the included SRs/MAs showed extremely low methodological and reporting quality. The results of the GRADE system indicated that the quality of most of the pooled evidence was very low. CHM may be beneficial in improving migraines and can be used as a complementary therapy. However, we should treat the conclusions of the evaluated SRs/MAs cautiously because of the low quality of evidence. Future SRs/MAs should focus on improving methodological and reporting quality. High-quality randomized controlled trials (RCTs) are needed to provide strong evidence for the efficacy of CHM treatment of migraines.

The strongly encourages the use of pharmaceutical-grade chemicals and analgesics. Sustained-release buprenorphine (SRB) is administered extralabel to rodents to mitigate moderate to severe pain. An FDA indexed buprenorphine formulation-extended-release buprenorphine (XRB)-has recently become available and is currently the only pharmaceutical-grade slow-release buprenorphine formulation approved for use in mice and rats. However, no studies have directly compared the pharmacokinetic parameters of SRB and XRB in surgically catheterized mice. To this end, we compared the plasma buprenorphine concentrations and pharmacokinetic parameters of SRB and XRB in mice after surgical catheterization. We hypothesized that mice treated before surgery with SRB or XRB would have circulating buprenorphine concentrations that exceeded the therapeutic threshold for as long as 72 h after surgery. Male and female C57Bl/6J mice were anesthetized, treated with a single dose of either SRB (1 mg/kg SC) or XRB (3.25 mg/kg SC), and underwent surgical catheterization. Arterial blood samples were collected at 6, 24, 48, and 72 h after administration. Weight loss after surgery (mean ± SEM) was similar between groups (SRB: males, 12% ± 2%; females, 8% ± 2%; XRB: males, 12% ± 1%; females, 8% ± 1%). Both SRB and XRB maintained circulating buprenorphine concentrations above the therapeutic level of 1.0 ng/mL for 72 h after administration. Plasma buprenorphine concentrations at 6, 24, and 48 h were significantly greater (3- to 4-fold) with XRB than SRB, commensurate with XRB's higher dose. These results support the use of either SRB or XRB for the alleviation of postoperative pain in mice. The availability of FDA-indexed XRB increases options for safe and effective pharmaceutical-grade analgesia in rodents.

Inflammation is the body's mechanism to trigger the immune system, thereby preventing bacteria and viruses from manifesting their toxic effect. Inflammation plays a vital role in regulating inflammatory mediator levels to initiate the wound healing process depending on the nature of the stimuli. This process occurs due to chemical release from white blood cells by elevating blood flow to the site of action, leading to redness and increased body temperature. Currently, there are numer-ous Non-steroidal anti-inflammatory drugs (NSAIDs) available, but these drugs are reported with adverse effects such as gastric bleeding, progressive kidney damage, and increased risk of heart at-tacks when prolonged use. For such instances, alternative options need to be adopted. The introduc-tion of voltage-gated ion channel blockers can be a substantial alternative to mask the side effects of these currently available drugs. Chronic inflammatory disorders such as rheumatoid and osteoarthri-tis, cancer and migraine, etc., can cause dreadful pain, which is often debilitating for the patient. The underlying mechanism for both acute and chronic inflammation involves various complex re-ceptors, different types of cells, receptors, and proteins. The working of voltage-gated sodium and calcium channels is closely linked to both inflammatory and neuropathic pain. Certain drugs such as carbamazepine and gabapentin, which are ion channel blockers, have greater pharmacotherapeutic activity for sodium and calcium channel blockers for the treatment of chronic inflammatory pain states. This review intends to provide brief information on the mechanism of action, latest clinical trials, and applications of these blockers in treating inflammatory conditions.

Osteoarthritis (OA) is disabling and degenerative disease of the joints that is clinically characterized by pain and loss of function. With no disease-modifying treatment available, current therapies aim at pain management but are of limited efficacy. Cannabis products, specifically cannabinoids, are widely used to control pain and inflammation in many diseases with no scientific evidence demonstrating their efficacy in OA. We investigated the effects of non-euphorigenic cannabis extracts, CBD oil and cannabigerol oil (CBG oil), on pain and disease progression in OA mice. Twelve-week-old male C57BL/6J mice received either sham or destabilization of the medial meniscus (DMM) surgery. DMM mice were treated with vehicle, CBD oil, or CBG oil. The gait of DMM mice was impaired as early as 2 weeks following surgery and continued deteriorating until week 8, which was restored by CBD oil and CBG oil treatments throughout the disease course. Mechanical allodynia developed in DMM mice, however, was not ameliorated by any of the treatments. On the other hand, both CBD oil and CBG oil ameliorated cold allodynia. In open field test, both oil treatments normalized changes in the locomotor activity of DMM mice. CBD oil and CBG oil treatments significantly reduced synovitis in DMM mice. Only CBG oil reduced cartilage degeneration, chondrocyte loss, and matrix metalloproteinase 13 expression, with a significant increase in the number of anabolic chondrocytes. Subchondral bone remodeling found in vehicle-treated DMM mice was not ameliorated by either CBD or CBG oil. Our results show evidence for the therapeutic efficacy of CBD oil and CBG oil, where both oils ameliorate pain and inflammation, and improve gait and locomotor activity in OA mice, representing clinical pain and function. Importantly, only CBG oil is chondroprotective, which may provide superior efficacy in future studies in OA patients.

Endocannabinoids have an important role for the regulation of neuropathic pain. In our previous study, we observed that preventing the degradation of a endocannabinoid, 2-arachidonoylglycerol (2-AG), using an inhibitor of monoacylglycerol lipase (JZL184), attenuated neuropathic orofacial pain (NOP). The present study aimed to investigate mechanisms underlying JZL184-induced attenuation of NOP. We hypothesized that JZL184 may suppress microglial reactivity in the trigeminal spinal subnucleus caudalis (Vc) under NOP. The infraorbital nerve (ION) was hemisected to model NOP in mice, resulting in a significant reduction of mechanical head-withdrawal threshold (MHWT) on day 4 following the ION hemisection. Chronic systemic application of JZL184 at a concentration of 8 or 16 mg/kg/day for 4 days significantly attenuated the reduction of MHWT in mice exposed to NOP. Administering JZL184 at 4 mg/kg/day or its vehicle, however, did not attenuate the MHWT of mice with NOP. The reactivity of microglial cells in the Vc increased in mice with NOP compared to sham-operated controls. The application of JZL184 at 8 or 16 mg/kg/day for 4 days significantly reduced the increased microglial reactivity in the Vc. The changes of microglia under NOP were, by contrast, not reduced by application of the drug at 4 mg/kg/day or its vehicle. The results indicate that preventing 2-AG degradation may increase its accumulation in the Vc and normalize microglial reactivity under NOP, which may contribute to suppressing NOP.

Mechanical allodynia impinges on the life quality of patients. Hen Egg Lysozyme (HEL) is a substance extracted from eggs that is commonly used to inhibit bacterial activity. The role of HEL in regulating and treating pain is unclear. Here, we find that HEL selectively attenuates static mechanical allodynia of mice induced by complete Freund's adjuvant (CFA), spinal nerve ligation (SNL) and chemotherapeutic agent. RNA-seq screening reveals that CFA significantly reduces the expression of Parkin in dorsal root ganglion (DRG) neurons of mice, while pre-administration of HEL increases the expression of Parkin and remits the static mechanical allodynia induced by Parkin-siRNA. Moreover, HEL increases the interaction between nuclear respiratory factor 1 (NRF1) and histone acetyltransferase P300 and then enhances the NRF1 mediated histone acetylation in prkn promoter region in DRGs of mice. Further, Parkin interacts with mechanotransducing ion channel TACAN (Tmem120a) and knockdown of Parkin significantly increases the membrane trafficking of TACAN in sensory neurons of mice. While pre-administration of HEL inhibits the increased membrane trafficking of TACAN in sensory neurons of mice induced by Parkin-siRNA. In addition, pre-given of HEL also significantly attenuates the static mechanical allodynia induced by overexpression of TACAN in mice, and the effect of HEL can be blocked by Parkin-siRNA. This indicates that HEL increases the expression of Parkin through epigenetic mechanisms and then decreases TACAN membrane trafficking in sensory neurons to relieve static mechanical hypersensitivity. Therefore, we reveal a novel function of HEL, which is a potential substance for the treatment of static mechanical pain.

Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics. It has been reported that enriched environment (EE), as a new way of endogenous pharmacotherapy, is effective in attenuating chronic inflammatory pain. However, the underlying molecular mechanisms are still not fully understood. NMDA NR2B receptor plays a critical role in pain transmission and modulation. Thus, in this study, we aimed at the effect of EE on the NR2B receptors expression in the prefrontal cortex, hippocampus and thalamus in the inflammatory pain mice. The results showed a significant increase of NR2B receptors in the thalamus of mice at 7 d following injection of CFA in the subcutaneous of the bottom of the left hind paw. EE significantly reduced the duration of mechanical hypersensitivity and anxiety-related behavior and the expression of NR2B receptors as compared to the standard condition. Furthermore, EE significantly increased 2-arachidonoylglycero (2-AG) levels at 7 d in the inflammatory pain mice as compared to the standard condition, and the effect of EE on the behavior and the expression of NR2B receptors was abolished by intraperitoneal injection of AM281 (a selective antagonist of CB1 receptor). Elevated 2-AG levels by intraperitoneal injection of JZL184 (a selective inhibitor of MAGL, the enzyme responsible for 2-AG hydrolysis) produced the same effect as EE. Results from this study provide the evidence that EE mimics endocannabinoids to take analgesic and anti-anxiety activities by decreasing the expression of the NR2B receptors via the CB1 receptor in the thalamus, pending further studies.

The A adenosine receptor (AAR) is a promising therapeutic target for inflammatory diseases, cancer, and chronic neuropathic pain, with agonists already in advanced clinical trials. Here we report an in-depth comparison of the pharmacological properties and structure-activity relationships of existing and expanded compound libraries of 2-substituted 1-imidazo[4,5-]quinolin-4-amine and 4-amino-substituted quinoline derivatives that function as AAR positive allosteric modulators (PAMs). We also show that our lead compound from each series enhances adenosine-induced AAR signaling preferentially toward activation of Gα and Gα isoproteins, which are coexpressed with the AAR in immune cells and spinal cord neurons. Finally, utilizing an extracellular/intracellular chimeric AAR approach composed of sequences from a responding (human) and a nonresponding (mouse) species, we provide evidence in support of the idea that the imidazoquinolin-4-amine class of PAMs variably interacts dually with the orthosteric ligand binding site as well as with a separate allosteric site located within the inner/intracellular regions of the receptor. This study has advanced both structural and pharmacological understanding of these two classes of AAR PAMs, which includes leads for future pharmaceutical development.

Chronic inflammation is implicated in numerous human pathologies. In particular, low-grade inflammation is currently recognized as an important mechanism of osteoarthritis (OA), at least in some patients. Among the signs of the inflammatory process are elevated macrophage numbers detected in the OA synovium compared to healthy controls. High macrophage counts also correlate with clinical symptoms of the disease. Macrophages are central players in the development of chronic inflammation, pain, cartilage destruction, and bone remodeling. However, macrophages are also involved in tissue repair and remodeling, including cartilage. Therefore, reduction of macrophage content in the joints correlates with deleterious effects in OA models. Macrophage population is heterogeneous and dynamic, with phenotype transitions being induced by a variety of stimuli. In order to effectively use the macrophage inflammatory circuit for treatment of OA, it is important to understand macrophage heterogeneity and interactions with surrounding cells and tissues in the joint. In this review, we discuss functional phenotypes of macrophages and specific targeting approaches relevant for OA treatment development.

Opioids are one of the most effective anti-nociceptive agents used in patients with cancer pain or after serious surgery in most countries. The endogenous opioid system participates in pain perception, but recently its role in inflammation was determined. κ-opioid receptors (KOP receptors), a member of the opioid receptor family, are expressed in the central and peripheral nervous system as well as on the surface of different types of immune cells, e.g. T cells, B cells and monocytes. In this review, we focused on the involvement of KOP receptors in the inflammatory process and described their function in a number of conditions in which the immune system plays a key role (e.g. inflammatory bowel disease, arthritis, subarachnoid hemorrhage, vascular dysfunction) and inflammatory pain. We summed up the application of known KOP ligands in pathophysiology and we aimed to shed new light on KOP receptors as important elements during inflammation.

Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs. CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARγ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, acute or chronic CIPN was introduced by short or long-term treatment of oxaliplatin in BALB/c mice. CIPN mice were treated with either a novel blood-brain barrier (BBB) penetrable PPARγ agonist ELB00824, or a BBB non-penetrable PPARγ agonist pioglitazone, or vehicle. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring byproducts of protein oxidation (carbonyl and 3-Nitrotyrosine) and lipid peroxidation [Thiobarbituric acid reactive substances (TBARS)], as wells as gene expression of Cat, Sod2, Ppargc1a. The effects of ELB00824 on nociceptor excitability were measured using whole-cell electrophysiology of isolated dorsal root ganglion neurons. Preemptive ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4 neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress.

Morphine is the most common drug of choice in clinical pain management; however, morphine tolerance presents a significant clinical challenge. The pathogenesis of morphine tolerance is known to be closely associated with angiotensin II receptor type 1 (AT1R) in microglia. As an AT1R antagonist, candesartan may serve an important role in regulating morphine tolerance. Therefore, the present study aimed to investigate the role of candesartan in morphine tolerance, and to explore the underlying mechanism. To meet this aim, BV2 microglial cells were treated with morphine or candesartan alone, or as a combination, and the expression levels of AT1R in BV2 cells were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. The levels of the inflammatory cytokines tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6 were subsequently detected by ELISA and western blotting. In addition, immunofluorescence analysis, western blotting and RT‑qPCR were used to detect the expression levels of the BV2 cell activation marker, ionized calcium‑binding adaptor molecule 1 (IBA‑1). Western blotting was also used to detect the expression levels of peroxisome proliferator‑activated receptor‑γ/AMP‑activated protein kinase (PPARγ/AMPK) signaling pathway‑associated proteins. Finally, the cells were treated with the PPARγ antagonist GW9662 and the AMPK inhibitor compound C to further explore the mechanism underlying the effects of candesartan on improving morphine tolerance. The expression levels of AT1R were revealed to be significantly increased following morphine induction; however, candesartan treatment inhibited the expression levels of AT1R, the levels of inflammatory cytokines and the protein expression levels of IBA‑1 in morphine‑induced BV2 cells in a dose‑dependent manner. These processes may be associated with activation of the PPARγ/AMPK signaling pathway. Taken together, the present study revealed that treatment with candesartan reduced morphine‑induced inflammatory response and cellular activation of BV2 cells via PPARγ/AMPK signaling.

Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease.

An estimated 54 million Americans currently suffer from debilitating arthritis. Patients who have exhausted conservative measures can be subject to chronic pain and resort to symptomatic management with anti-inflammatories, acetaminophen, and opioids. Cannabidiol (CBD) is a non-psychoactive cannabinoid that has shown promise in preclinical studies to reduce inflammation and pain associated with arthritis. The purpose of this study was to explore patient perceived effects of cannabidiol on symptoms of arthritis.