Pharmacology/Drug Development

This review was designated to evaluate the efficacy of parenteral ketorolac in treating acute migraine headache.

Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens. However, signaling pathways downstream to these receptors in dorsal root ganglion (DRG) neurons are not yet understood. We found that Anoctamin 1 (ANO1), a Ca2+-activated chloride channel, is a transduction channel mediating Mrgprs-dependent itch signals. Genetic ablation of Ano1 in DRG neurons displayed a significant reduction in scratching behaviors in response to acute and chronic Mrgprs-dependent itch models and the epidermal hyperplasia induced by dry skin. In-vivo Ca2+ imaging and electrophysiological recording revealed that chloroquine and other agonists of Mrgpr receptors excited DRG neurons via ANO1. More importantly, the overexpression of Ano1 in DRG neurons of Ano1-deficient mice rescued the impaired itching observed in Ano1-deficient mice. These results demonstrate that ANO1 mediates the Mrgprs-dependent itch signaling in pruriceptors and provides clues to treating pathologic itch syndromes.

Total joint arthroplasties are among the most common elective procedures in the United States, and they are associated with postoperative pain. Gabapentin enacarbil is a prodrug with an extended-release formulation that has been proposed for multimodal postoperative analgesia, but the drug's efficacy for major arthroplasties remains unclear.

Bee Venom (BV) has been used to treat rheumatoid arthritis (RA) for many centuries. However, its clinical use is limited by pain and fear of bee stings/injection. Nanoemulsions (NEs) are nanocarriers that are able to help their content(s) penetrate through the skin. They also act as drug reservoirs on the skin to provide an efficient, sustained-release vehicle.

The anti-diabetic drug metformin has been shown to reduce pain hypersensitivity in preclinical models of chronic pain and in neuropathic pain in humans. Multiple intracellular pathways have been described as metformin targets. Among them, metformin is an activator of the adenosine 5'-monophosphate protein kinase (AMPK) that can in turn modulate the activity of the E3 ubiquitin ligase NEDD4-2 and thus posttranslational expression of voltage gated sodium channels (Nas). In this study, we found that the bulk of the effect of metformin on Na1.7 is dependent on NEDD4-2. In HEK cells, the expression of Na1.7 at the membrane fraction, obtained by a biotinylation approach, is only reduced by metformin when co-transfected with NEDD4-2. Similarly, in voltage clamp recordings, metformin significantly reduced Na1.7 current density when co-transfected with NEDD4-2. In mouse dorsal root ganglion (DRG) neurons, without changing the biophysical properties of Na1.7, metformin significantly decreased Na1.7 current densities, but not in Nedd4L knockout mice ( ). In addition, metformin induced a significant reduction in NEDD4-2 phosphorylation at the Serine 328 residue in DRG neurons, an inhibitory phosphorylation site of NEDD4-2. In current clamp recordings, metformin reduced the number of action potentials elicited by DRG neurons from , with a partial decrease also present in mice, suggesting that metformin can also change neuronal excitability in an NEDD4-2-independent manner. We suggest that NEDD4-2 is a player for the effect of metformin on the excitability of nociceptive neurons; this action may contribute to the relief of neuropathic pain.Metformin is a multi-target, anti-diabetic drug that has shown therapeutic potential to reduce neuropathic pain. The intracellular mechanisms leading to a reduction in hyperexcitability and pain hypersensitivity remain unclear. We found that metformin acts through the activity of the E3-ubiquitin ligase NEDD4-2 to reduce cell surface expression and currents of voltage gated sodium channels (Nas), especially the Na1.7 isoform. In current clamp experiments, metformin reduced the DRG neuron firing frequency, with a smaller effect in knockout mice ( ). On the other hand, NEDD4-2 is indispensable for the metformin effect on the rheobase and the resting membrane potential of DRG neurons. These results suggest that NEDD4-2 activity is a crucial actor, although not exclusive, to reduce the excitability of nociceptive neurons.

Management of neuropathic cancer pain (NCP) refractory to regular opioids remains an important challenge. The efficacy of pregabalin for NCP except chemotherapy-induced peripheral neuropathy (CIPN) has already been confirmed in two randomised controlled trials (RCTs) compared with placebo. Duloxetine offers the potential of analgesia in opioid refractory NCP. However, there are no RCT of duloxetine for the management of opioid-refractory NCP as a first line treatment. Both classes of drugs have the potential to reduce NCP, but there has been no head-to-head comparison for the efficacy and safety, especially given differing side effect profiles.