Pharmacology/Drug Development

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.

Some 30-50% of the global population and almost 20% of the European population actually suffer from chronic pain, which presents a tremendous burden to society when this pain turns into a disability and hospitalization. Palmitoylethanolamide (PEA) has been demonstrated to improve pain in preclinical contexts, but an appraisal of clinical evidence is still lacking. The present study aimed at addressing the working hypothesis for the efficacy of PEA for nociceptive musculoskeletal and neuropathic pain in the clinical setting. The systematic search, selection and analysis were performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations. The primary outcome was pain reduction, as measured by a pain assessment scale. The secondary outcome was improvement in quality of life and/or of parameters of function. The results obtained for a total of 933 patients demonstrate the efficacy of PEA over the control ( < 0.00001), in particular in six studies apart from the two randomized, double-blind clinical trials included. However, the results are downgraded due to the high heterogeneity of the studies (I = 99%), and the funnel plot suggests publication bias. Efficacy in achieving a reduction in the need for rescue medications and improvement in functioning, neuropathic symptoms and quality of life are reported. Therefore, adequately powered randomized, double-blind clinical trials are needed to deepen the domains of efficacy of add-on therapy with PEA for chronic pain. PROSPERO registration: CRD42022314395.

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.

Aging is a risk factor for the development of osteoarthritis (OA), a progressive joint disease leading to cartilage damage, pain, and loss of function. In a mouse model of OA, senolytic drugs to selectively clear senescent cells (SnCs) that accumulate with injury or aging yielded a chondroprotective effect; however, this therapeutic benefit was limited in aged mice. Due to inconsistency between cartilage destruction and pain-associated symptoms, we studied the therapeutic effect of senolytics on joint pain in spontaneous OA. We orally treated 21- and 22-month old mice with an ABT263 and Dasatinib and Quercetin (D+Q) drug combination. Selective elimination of the SnCs that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. Selective removal of the SnCs from cultures of synovial cells from human OA patients also decreased expression of senescent markers, axonal growth-promoting factors, such as NGF, and angiogenesis markers. We suggest that systemic administration of ABT263 and D+Q is an exciting therapeutic approach to age-related OA pain.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model.

Sensitization of central pain and inflammatory pathways play essential roles in migraine, a primary neurobiological headache disorder. Since hypoxia-inducible factor-1α (HIF-1α) is implicated in neuroprotection and inflammation inhibition, herein we investigated the role of HIF-1α in migraine. A chronic migraine model was established in mice by repeated injection of nitroglycerin (10 mg/kg, i.p.) every other day for 5 total injections. In the prevention and acute experiments, roxadustat, a HIF-1α stabilizer, was orally administered starting before or after nitroglycerin injection, respectively. Pressure application measurement, and tail flick and light-aversive behaviour tests were performed to determine the pressure pain threshold, thermal nociceptive sensitivity and migraine-related light sensitivity. At the end of experiments, mouse serum samples and brain tissues were collected for analyses. We showed that roxadustat administration significantly attenuated nitroglycerin-induced basal hypersensitivity and acute hyperalgesia by improving central sensitization. Roxadustat administration also decreased inflammatory cytokine levels in serum and trigeminal nucleus caudalis (TNC) through NF-κB pathway. Consistent with the in vivo results showing that roxadustat inhibited microglia activation, roxadustat (2, 10, and 20 μM) dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway. Taken together, this study demonstrates that roxadustat administration ameliorates migraine-like behaviours and inhibits central pain sensitization in nitroglycerin-injected mice, which is mainly mediated by HIF-1α/NF-κB/inflammation pathway, suggesting the potential of HIF-1α activators as therapeutics for migraine.

Chronic low back pain is prevalent, highly disabling and a relevant socioeconomic health concern. Although allocated to placebo groups, patients in randomized controlled trials show significant pain relief, pointing to the relevance of placebo effects. Overcoming ethical and legal concerns related to deceptive placebos, recent studies have demonstrated the efficacy of short-term treatments for chronic low back pain with open-label (i.e., non-deceptive) placebos. However, data on long-term efficacy of open-label placebos are sparse. Here, we report a three-year follow-up of our previously published randomized controlled trial demonstrating pain reduction, improvement in disability and depressive symptoms after a three-week treatment with open-label placebos. Including records from N=89 previously enrolled patients, we investigated changes between the groups with and without previous open-label placebo treatment in pain intensity (primary outcome), disability and mood (secondary outcomes), biopsychosocial factors and lifestyle (exploratory outcomes) from parent baseline to follow-up. Over the three-year period, there were no differences in any outcome between groups with and without open-label placebo treatment. Therefore, our follow-up data do not support the previously suggested assumption that a three-week open-label placebo treatment has long-term effects. This study was pre-registered on April 14, 2020, in the German Clinical Trials Register (registration number DRKS00021405).

Pain is one of the most common concomitant symptoms among cancer patients. Pharmacologic agents are regarded as a cornerstone of cancer pain management. 'Dose titration' with short-acting morphine is widely accepted. Such a titration method is very complicated. The analgesic background establishment is often delayed. Titration based on sustained-release opioids is also recommended, but the onset of analgesic effect requires hours, whereas the rescue analgesia is always needed. This study evaluated the optimized morphine titration scheme with a simultaneous combination of sustained-release morphine and subcutaneous morphine.