Background/Objectives: Neuropathic pain (NP) affects approximately 6.9–10% of the population and is inadequately managed by the current therapies, as reflected by a high number needed to treat (NNT). These data highlight the socio-economic burden of NP on healthcare. Thus, the repurposing of existing medications and new drug combinations to enhance therapeutic efficacy are required. Methods/Results: Here, we show that intrathecal phenylephrine (PE) in a dose of 3, 10, or 30 nmol/rat acutely alleviates tactile allodynia in rats with mononeuropathic pain evoked by partial sciatic nerve ligation. Prazosin and idazoxan, which are considered as selective α₁- and α₂-adrenoreceptor antagonists, respectively, reversed the antiallodynic effects of PE. In ex vivo experiments, PE induced a significant cytosolic [³H]-noradrenaline release from mouse spinal tissue. In addition, in the mouse vas deferens, PE produced smooth muscle contraction in prazosin and idazoxan sensitive manner. As a novelty, in another set of experiments, oral PE (5 mg/kg) and pregabalin (PGB, 25 mg/kg) combination, but not the individual drug treatments, acutely alleviated allodynia in rats with mononeuropathy. In addition, the antiallodynic action of the combination was further enhanced upon chronic treatment. Under isoflurane anesthesia, this combination was devoid of cardiovascular side effects attributed to systolic and diastolic blood pressure, mean arterial pressure, or heart rate. PGB induced motor dysfunction was not altered upon the combination with PE. Conclusions: These data suggest that PE in combination with PGB shows promise in preclinical settings; however, the necessity for further studies is paramount to detail the pharmacokinetic interactions involved.

The current pharmacological approach for the treatment of opioid use disorder (OUD), as a result of prescription misuse or illicit opioids, utilises opioid ligands that have either an agonist or antagonist profile. In this context, methadone and buprenorphine act as opioid agonists, whereas naltrexone functions as an opioid antagonist. To decrease the reinforcing effects of illicit opioids, higher doses of methadone and buprenorphine have been recommended, but this is associated with increased side effects. Therefore, several preclinical efforts have been carried out over the last decades to find drugs that act on receptors other than opioid receptors. A large body of preclinical evidence has shown the ability of N-methyl-D-aspartate receptor (NMDAR) antagonists like ketamine to treat opioid addiction behaviours in animals. Indeed, ketamine by itself is an addictive drug; thus, the treatment of OUD is still a matter to be solved. Growing data position glycine transporter 1 as a possible therapeutic target for the treatment of substance use disorder. This transporter regulates the reuptake of glycine, which can modulate the function of both NMDARs and GPR158, a metabotropic glycine receptor (mGlyR); thus, it is worth investigating in the management of OUD. To gain insight into the role of glycinergic transmission in OUD, alongside NMDAR-mediated glutamatergic transmission, dopaminergic and GABAergic transmission were also reviewed.

Trace amine-associated receptors (TAARs) are a class of G protein-coupled receptors with roles in olfaction, behaviour, and immunity. Known best as an olfactory receptor, TAAR5 has been linked to emotional behaviour and hippocampal neurogenesis, yet its peripheral mechanisms remain poorly understood. Given bidirectional influences between the gut microbiota and the host, we investigated whether TAAR5 deletion alters the gut microbiome in mice. Using 16S rRNA sequencing, we compared the gut microbiota of TAAR5-knockout (TAAR5-KO) and wild-type mice. While alpha-diversity remained unchanged, beta-diversity analysis revealed significant separation between genotypes, with TAAR5-KO mice exhibiting markedly increased inter-individual variability. Taxonomically, KO mice showed a significant reduction in Ruminococcus and ASF356, alongside an enrichment of specific Lachnospiraceae and Prevotellaceae lineages. Functional metagenomic prediction (PICRUSt2) implied a reduction in the metagenomic capacity for central metabolic pathways (glycolysis, TCA cycle, fatty acid β-oxidation) and an increase in the capacity for guanosine nucleotide degradation pathways; these hypotheses remain untested. Molecular docking identified candidate microbial metabolites, including small amines (2-aminophenol, aminoacetone, butan-1-amine), with ligand efficiencies comparable to the known TAAR5 agonist trimethylamine. These findings suggest that TAAR5 may influence gut microbiome composition and function, with particular impact on Ruminococcus—a genus linked to intestinal inflammation. The increased compositional variability in TAAR5-KO mice suggests that TAAR5 may act as a homeostatic gatekeeper in gut microbial ecology. Our in silico results offer testable hypotheses for future validation of microbial metabolites as novel TAAR5 ligands.