Pharmacology/Drug Development

Chronic pelvic pain conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) remain clinical and mechanistic enigmas. Microglia are resident immune cells of the central nervous system (CNS) that respond to changes in the gut microbiome, and studies have linked microglial activation to acute and chronic pain in a variety of models, including pelvic pain. We have previously reported that mice deficient for the lipase acyloxyacyl hydrolase (AOAH) develop pelvic allodynia and exhibit symptoms, comorbidities, and gut dysbiosis mimicking IC/BPS. Here, we assessed the role of AOAH in microglial activation and pelvic pain. RNAseq analyses using the ARCHS4 database and confocal microscopy revealed that AOAH is highly expressed in wild type microglia but at low levels in astrocytes, suggesting a functional role for AOAH in microglia. Pharmacologic ablation of CNS microglia with PLX5622 resulted in decreased pelvic allodynia in AOAH-deficient mice and resurgence of pelvic pain upon drug washout. Skeletal analyses revealed that AOAH-deficient mice have an activated microglia morphology in the medial prefrontal cortex and paraventricular nucleus, brain regions associated with pain modulation. Because microglia express Toll-like receptors and respond to microbial components, we also examine the potential role of dysbiosis in microglial activation. Consistent with our hypothesis of microglia activation by leakage of gut microbes, we observed increased serum endotoxins in AOAH-deficient mice and increased activation of cultured BV2 microglial cells by stool of AOAH-deficient mice. Together, these findings demonstrate a role for AOAH in microglial modulation of pelvic pain and thus identify a novel therapeutic target for IC/BPS.

The restricted duration is a fundamental drawback of traditional local anesthetics during postoperative pain from a single injection. Therefore, an injectable local anesthetic that produces repeatable on-demand nerve blocks would be ideal.

TRPM3 is a calcium-permeable cation channel expressed in a range of sensory neurons that can be activated by heat and the endogenous steroid pregnenolone sulfate (PS). During inflammation, the expression and function of TRPM3 are both augmented in somatosensory nociceptors. However, in isolated dorsal root ganglion (DRG) neurons application of inflammatory mediators like prostaglandins and bradykinin (BK) inhibit TRPM3. Therefore, the aim of this study was to examine the effect of preceding activation of cultured 1 day old mouse DRG neurons by the inflammatory mediator BK on TRPM3-mediated calcium responses. Calcium signals were recorded using the intensity-based dye Fluo-8. We found that TRPM3-mediated calcium responses to PS were enhanced by preceding application of BK in cells that responded to BK with a calcium signal, indicating BK receptor (BKR) expression. The majority of cells that co-expressed TRPM3 and BKRs also expressed TRPV1, however, only a small fraction co-expressed TRPA1, identified by calcium responses to capsaicin and supercinnamaldehyde, respectively. Signaling and trafficking pathways responsible for sensitization of TRPM3 following BK were characterized using inhibitors of second messenger signaling cascades and exocytosis. Pharmacological blockade of protein kinase C, calcium-calmodulin-dependent protein kinase II and diacylglycerol (DAG) lipase did not affect BK-induced sensitization, but inhibition of DAG kinase did. In addition, release of calcium from intracellular stores using thapsigargin also resulted in TRPM3 sensitization. Finally, BK did not sensitize TRPM3 in the presence of exocytosis inhibitors. Collectively, we show that preceding activation of DRG neurons by BK sensitized TRPM3-mediated calcium responses to PS. Our results indicate that BKR-mediated activation of intracellular signaling pathways comprising DAG kinase, calcium and exocytosis may contribute to TRPM3 sensitization during inflammation.

Elimination or blocking of astrocytes could ameliorate neuropathic pain in animal models. MiR-125a-5p, expressed in astrocyte derived extracellular vesicles, could mediate astrocyte function to regulate neuron communication. However, the role of miR-125a-5p in DPN (diabetic peripheral neuropathy) remains elusive.

Intra-articular injections of hyaluronic acid (HA), the United States Food and Drug Administration approved treatment and widely utilized to delay or reserve the progression of the osteoarthritis (OA) involves. However, this treatment has shown controversial results through various clinical practice guidelines and meta-analysis evaluations, warrants more advanced researches on its safety and effectiveness.

For decades, chronic pain was managed with an almost conventional approach of using a wide range of analgesic spectrum, surgical approaches and complex interventional pain techniques to modulate or even interrupt pain pathways. These different approaches carry many pharmacological hazards together with the lack of efficacy and safety of many interventional and surgical management techniques for chronic pain have mandated searching for other effective therapies including alternative treatments. Cannabinoids are naturally occurring substances that are derived from Cannabis sativa L. The usage of cannabinoids and their related synthetic chemical compounds has emerged as a choice in the management of different chronic pain conditions is being evaluated, however, the efficacy is still not consistently established. In the present investigation, therefore, we discuss the different aspects related to cannabinoids and their implications in the management of chronic pain conditions. This review will also discuss the safety profile of the cannabinoids together with the legal considerations that hinder their use in different countries.

Diacerein (DCN), an analogue of rhein (a glycosidal compound of natural origin), is currently used in the treatment of osteoarthritis and is given a fast-track designation for development to treat epidermolysis bullosa (EB). It is a nonsteroidal anti-inflammatory drug having disease-modifying properties in osteoarthritis and anti-inflammatory effects for the treatment of EB. Diacerein has a beneficial effect on pain relief and demonstrated antioxidant and anti-apoptotic effects, which are useful in renal disease, diabetes, and other disorders. This review discusses the possible mechanism of diacerein in the management of pain. The potential role of rhein and diacerein in the treatment of neuropathic, inflammatory and nociceptive pain is also reviewed. The effect of diacerein and rhein on mediators of pain, such as transient receptor potential cation channel subfamily V (TRPV1), Substance P, glutamate, inflammatory cytokines, nitric oxide, matrix metalloproteinases, histamine, palmitoylethanolamide, nuclear factor-kappa B (NFkB), and prostaglandin, has also been discussed. The data highlights the role of diacerein in neuropathic, nociceptive and inflammatory pain. Clinical trials and mechanism of action studies are needed to ascertain the role of diacerein, rhein or their analogues in the management of pain, alone or in combination with other approved therapies.