Pharmacology/Drug Development

Neuronal progranulin (PGRN) overexpression is an endogenous adaptive pain defense following nerve injury. It allows the survival of injured neurons to block enhanced nociceptive responses. Trimetazidine (TMZ) is widely used by cardiac patients as an anti-anginal drug, reflecting its anti-ischemic property. TMZ promotes axonal regeneration of sciatic nerves after crush injury. This study explored the interplay between PGRN and extracellular signal-regulated kinases (ERK1/2) to address mechanisms underlying neuropathic pain alleviation following paclitaxel (PTX) administration. Rats were given four injections of PTX (2 mg/kg, i.p.) every other day. Two days after the last dose, rats received TMZ (25 mg/kg) with or without the ERK inhibitor, PD98059, daily for 21 days. TMZ preserved the integrity of myelinated nerve fibers, as evidenced by an obvious reduction in axonal damage biomarkers. Accordingly, it alleviated PTX-evoked thermal, cold, and mechanical hyperalgesia/allodynia. TMZ also promoted ERK1/2 phosphorylation with a profound upsurge in PGRN content. These effects were associated with a substantial increase in Notch1 receptor gene expression and a prominent anti-inflammatory effect with a marked increase in mRNA expression of secretory leukocyte protease inhibitor. Further, TMZ decreased oxidative stress and caspase-3 activity in the sciatic nerve. Conversely, co-administration of PD98059 completely abolished these beneficial effects. Thus, the robust antinociceptive effect of TMZ is largely attributed to upregulating PGRN and Notch1 receptors via ERK1/2 activation.

HIV continues to be a critical health issue for sexual minority men (SMM) in the USA. Chronic pain is common in individuals with HIV, including older SMM, and is associated with substance use behaviors. This cross-sectional study sought to address a gap in the literature by characterizing interrelationships among chronic pain, substance use disorders (SUDs), medication adherence, and engagement in HIV care among older (≥50) SMM living with HIV and chronic pain (N = 63). The unadjusted relationship between an opioid use disorder and pain indicated that participants with an opioid use disorder reported higher pain ratings than those without. Presence of alcohol use disorder was significantly associated with missed HIV-care appointments due to chronic pain or substance use, showing that individuals with an alcohol use disorder reported more missed appointments in the past year. Higher pain was significantly associated with the same missed appointments variable, such that those reporting higher pain ratings also reported more missed appointments in the past year. These findings provide preliminary evidence of the interrelationships among chronic pain, SUDs, and engagement in HIV care among older SMM living with HIV and suggest that pain management in this population might support fuller engagement in HIV care.

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient's quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named and , and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with and (30-100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of and repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, and ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, and have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, and reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.

The aim of this study was to provide an overview of clinical studies on calcitonin gene-related peptide (CGRP) measurements in body fluids of migraine patients and to discuss the validity of CGRP measurement as a clinical biomarker of migraine.

Treating chronic pruritus is challenging for dermatologists due to the lack of therapeutic options. We review the effects of κ-opioid receptor (KOR) and μ-opioid receptor (MOR) in the modulation of itch, summarize evidence supporting the efficacy and safety of opioid receptor-targeting agents in chronic pruritus, and address clinical considerations.

Intranasally administered non-steroidal anti-inflammatory drugs (NSAIDs) offer an innovative opportunity in the field of pain management. Combination of the nasal physiological advantages such as the rich vascularization and large absorption area along with novel nanomedical formulations can fulfill all the necessary criteria of an advanced drug delivery system. Nanoemulsions represent a versatile formulation approach suitable for nasal drug delivery by increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery due to their stability, small droplet size and optimal solubilization properties. In this study we aimed to develop meloxicam (MX)-loaded mucoadhesive nanoemulsions and to investigate the nasal applicability of the optimized formulations. Our results indicated the optimized nanoemulsion formulation (MX-NE3) had a droplet size of 158.5 nm in monodisperse droplet size distribution (polydispersity index of 0.211). The surface charge was -11.2 mV, which helped with the colloidal stability upon dilution at simulated nasal conditions and storage. The high encapsulation efficiency (79.2%) mediated a 15-fold drug release and a 3-fold permeability increase at nasal conditions compared to the initial MX. Proper wetting properties associated with high mucoadhesion prosper the increased residence time on the surface of the nasal mucosa. No cytotoxic effect of the formulations was observed on NIH/3T3 mouse embryonic fibroblast cell lines, which supports the safe nasal applicability.

Buprenorphine has been widely used in opioid medication assisted treatment (MAT) in the past decade. However, due to misinterpretation of its intrinsic mu opioid receptor activity extrapolated from preclinical and animal data, buprenorphine's clinical application in pain management has been greatly limited. Buprenorphine acts as a full mu agonist with fewer side effects compared to traditional opioids and can be effectively used in the treatment of acute and chronic pain. A strong body of evidence demonstrates that buprenorphine is an effective analgesic agent in both adult and pediatric surgical patients. In addition, buprenorphine has been successfully used in treating chronic pain, particularly in cancer pain and neuropathic pain. In this Journal course, buprenorphine's receptor pharmacology and pharmacokinetics are reviewed. Specifically, misinterpretation of its intrinsic mu receptor activity, and both analgesic ceiling effect and efficacy are clarified. Differences between suboxone and buprenorphine, and specific applications are explained. Pain management options and guidelines for surgical patients on buprenorphine are discussed, as well.