Pharmacology/Drug Development

Anticancer drug paclitaxel (PTX) frequently causes painful peripheral neuropathy; however, no medication has been shown to be effective in the treatment of this debilitating side effect. We aimed to investigate the efficacy of two different doses of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) on PTX-induced mechanical allodynia and spinal cytokine levels and their localization to target tissues such as the spinal cord and sciatic nerve. After the development of mechanical allodynia with repeated PTX administration, two different doses of rat BM-MSCs, low or high (1 × 10 -5 × 10 ), were transplanted into rats and the evaluation continued for 30 days. Interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-10 levels in spinal cord samples of animals were analyzed by enzyme-linked immunosorbent assay. PTX-induced mechanical allodynia was relieved significantly 15 days after the transplantation of high-dose of BM-MSCs. Both MSCs doses were effective in alleviating allodynia, but the onset of effect was earlier with the high dose. High-dose of BM-MSCs significantly decreased spinal IL-1β and TNF-α levels compared to the PTX group. Fluorescent dye-labeled BM-MSCs were observed much more frequently in the sciatic nerve and spinal cord samples of the high-dose BM-MSCs transplanted group than in the low-dose group animals. In conclusion, we found that the antiallodynic effects of BM-MSCs appeared earlier when high-dose of cells were administered. We think that other mechanisms may play a role in the effects of MSCs, besides localization to damaged tissues and reducing spinal inflammatory cytokine levels. We show that BM-MSCs can be a novel approach in PTX-induced mechanical allodynia.

Migraine is a primary headache with genetic susceptibility, but the pathophysiological mechanisms are poorly understood, and it remains an unmet medical need. Earlier we demonstrated significant differences in the transcriptome of migraineurs' PBMCs (peripheral blood mononuclear cells), suggesting the role of neuroinflammation and mitochondrial dysfunctions. Post-transcriptional gene expression is regulated by miRNA (microRNA), a group of short non-coding RNAs that are emerging biomarkers, drug targets, or drugs. MiRNAs are emerging biomarkers and therapeutics; however, little is known about the miRNA transcriptome in migraine, and a systematic comparative analysis has not been performed so far in migraine patients.

Chronic itch is one of the most prominent clinical characteristics of diverse systematic diseases. It is a devastating sensation in pathological diseases. Despite its importance, there are no FDA-labelled drugs specifically geared toward chronic itch. The associated complex pathogenesis and diverse causes escalate chronic itch to being one of the top challenges in healthcare. Humanized antibodies against IL-13, IL-4, and IL-31 proved effective in treatment of itch-associated atopic dermatitis but remain to be validated in chronic itch. There are still no satisfactory anti-itch therapeutics available toward itch-related neuropeptides including GRP, BNP, SST, CGRP, and SP. The newly identified potential itch targets including OSM, NMB, glutamate, periostin, and Serpin E1 have opened new avenues for therapeutic development. Proof-of-principle studies have been successfully performed on antagonists against these proteins and their receptors in itch treatment in animal models. Their translational interventions in humans need to be evaluated. It is of great importance to summarize and compare the newly emerging knowledge on chronic itch and its pathways to promote the development of novel anti-itch therapeutics. The goal of this review is to analyze the different physiologies and pathophysiologies of itch mediators, whilst assessing their suitability as new targets and discussing future therapeutic development.

Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B in relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in mice with streptozotocin-induced PDN. We examined metformin's efficacy following oral (acute and prolonged 7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a single oral dose, whereas vitamin B was intraperitoneally administered for 7 days. In combination experiments, metformin (prolonged treatment) and analgesics/vitamin B were co-administered in fixed-dose fractions of their ED values and the type of interaction was determined using isobolographic analysis. Metformin produced dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B also dose-dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises with analgesics/vitamin B, with a 6-7 fold dose reduction of both drugs in the examined combinations. In conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and peripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B in reducing hyperalgesia. Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer) analgesic doses for treating PDN. Combined metformin-vitamin B use may provide more effective pain relief and mitigate metformin-induced vitamin B deficiency.

Opioids like fentanyl remain the mainstay treatment for chronic pain. Unfortunately, opioid's high dependence liability has led to the current opioid crisis, in part, because of side-effects that develop during long-term use, including analgesic tolerance and physical dependence. Both tolerance and dependence to opioids may lead to escalation of required doses to achieve previous therapeutic efficacy. Additionally, altered sleep and circadian rhythms are common in people on opioid therapy. Opioids impact sleep and circadian rhythms, while disruptions to sleep and circadian rhythms likely mediate the effects of opioids. However, the mechanisms underlying these bidirectional relationships between circadian rhythms and opioids remain largely unknown. The circadian protein, neuronal PAS domain protein 2 (NPAS2), regulates circadian-dependent gene transcription in structure of the central nervous system that modulate opioids and pain. Here, male and female wild-type and NPAS2-deficient (NPAS2-/-) mice were used to investigate the role of NPAS2 in fentanyl analgesia, tolerance, hyperalgesia and physical dependence. Overall, thermal pain thresholds, acute analgesia and tolerance to a fixed dose of fentanyl were largely similar between wild-type and NPAS2-/- mice. However, female NPAS2-/- exhibited augmented analgesic tolerance and significantly more behavioral symptoms of physical dependence to fentanyl. Only male NPAS2-/- mice had increased fentanyl-induced hypersensitivity, when compared with wild-type males. Together, our findings suggest sex-specific effects of NPAS2 signaling in the regulation of fentanyl-induced tolerance, hyperalgesia and dependence.

S-nitrosothiols exert multiple effects on neural processes in the central and peripheral nervous system. This study shows that intravenous infusion of S-nitroso-L-cysteine (SNO-L-CYS, 1 μmol/kg/min) in anesthetized male Sprague Dawley rats elicits (a) sustained increases in minute ventilation, via increases in frequency of breathing and tidal volume, (b) a decrease in Alveolar-arterial (A-a) gradient, thus improving alveolar gas-exchange, (c) concomitant changes in arterial blood-gas chemistry, such as an increase in pO and a decrease in pCO, (d) a decrease in mean arterial blood pressure (MAP), and (e) an increase in tail-flick (TF) latency (antinociception). Infusion of S-nitroso-D-cysteine (SNO-D-CYS, 1 μmol/kg/min, IV), did not elicit similar responses, except for a sustained decrease in MAP equivalent to that elicited by SNO-L-CYS. A bolus injection of morphine (2 mg/kg, IV) in rats receiving an infusion of vehicle elicited (a) sustained decreases in frequency of breathing tidal volume, and therefore minute ventilation, (b) a sustained decrease in MAP, (c) sustained decreases in pH, pO and maximal sO with sustained increases in pCO and A-a gradient, and (d) a sustained increase in TF latency. In rats receiving SNO-L-CYS infusion, morphine elicited markedly smaller changes in minute ventilation, arterial blood gas chemistry, A-a gradient and MAP. In contrast, the antinociceptive effects of morphine were enhanced in rats receiving the infusion of SNO-L-CYS. The morphine-induced responses in rats receiving SNO-D-CYS infusion were similar to vehicle-infused rats. These data are the first to demonstrate that infusion of an S-nitrosothiol, such as SNO-L-CYS, can stereoselectively ameliorate the adverse effects of morphine on breathing and alveolar gas exchange while promoting antinociception.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post-hoc analysis of two phase III studies in patients with PsA treated with tofacitinib assessed dactylitis by location, and the impact on patient-reported outcomes (PROs).

Patients who have perioperatively benefited from regional anesthesia frequently report moderate to severe pain when the nerve block effects fade away. Over the past years, the term "rebound pain" has been introduced, suggesting a specific pathologic process. It is debated whether significant pain on block resolution reflects a separate and distinct pathologic mechanism potentially involving proinflammatory and neurotoxic effects of local anesthetics, or is simply caused by the recovery of sensory function at a timepoint when nociceptive stimuli are still intense, and moderate to severe pain should be anticipated. In that latter case, the phenomenon referred to as rebound pain could be considered a failure of pain management providers to devise an adequate analgesia plan. Whatever the ultimate designation, management of rebound pain should be proactive, by implementing multimodal analgesia, or tailoring the blockade to the expected trajectory of postoperative pain and managing patient expectations accordingly. Until we know more about the etiology and impact of this phenomenon, the authors suggest a more neutral designation such as "pain on block resolution."