Taking up the line from the first EFIC day, another poster dives into NaV1.8-associated topics. Nicolas Dumaire and colleagues present data on trafficking of NaV1.8 channels. In vivo and in vitro data suggest CRMP5, an axonal guidance protein to serve as adaptor for E3 ligases and inhibitor for deubiquitinase. Gaining more and more insight into the MoA of NaV1.8 channel function will enable generation of hypotheses along the new clinically proven NaV1.8 channel blockers (III-A.45). More NaV-channel insight is provided by Marie Mehlfeldt and colleagues, as action potentials in mechanoinsensitive C fibers and Aδ fibers are driven by NaV1.9 (upstroke, shoulder), NaV1.8 (overshoot) and NaV1.7 (upstroke) based on patch-clamp experiments and computational modeling (III-B.30). Finally, Phase I (SAD/MAD) data on ODM-111, a novel NaV1.8 blocker from Orion is presented by Valteri Aho and colleagues. Experimental pain tests and placebo were included and revealed efficacy in the cold pressor test but not in other tests. The data were used for PKPD analysis and based on CTIS ODM-111 is in phase II studies in patients with DPN and knee OA (III-D1.W.04).
While the contribution of C and Aδ afferents to pain signaling is well known, Aβ afferents are better known for their role in discriminative touch. Otmane Bouchatta and colleagues present microneurography data generated in human volunteers showing a phenotype switch for Aβ fibers upon heat-induced local skin inflammation. Under these conditions, Aβ fibers become brush-responsive and thus might contribute to tactile allodynia in chronic pain (III-B.37).
A good conference saves the best until last. Thus, a number of novel potential drug candidates emerge on the last day. Somatostatin has long been discussed in the context of pain. Now, Valeria Tekus and colleagues from algonist present data on selective SST4 agonists. Selectivity was demonstrated by cAMP level decrease in SST4R but not in SST2R expressing CHO cells in vitro. Efficacy in mouse models of neuropathic (PNL) and inflammatory pain (MIA) suggest potential of these drug candidates as novel analgesics. Curios to follow the upcoming translational strategy (III-D1.W.02). Océane Boyer and colleagues present a new compound active in RF amide field. A selective PrPRP antagonist with nanomolar affinity was isolated and characterized in vitro and in vivo. The compound is centrally available and anti-hyperalgesic in mouse models of inflammatory and neuropathic pain (III-D1.W.07). Neil Benson from Sevenless shows PKPD data suggesting efficacy of BI3406, a SOS1 inhibitor in a mouse intraplantar CFA weight bearing paradigm. Thus, targeting this part of the NGF pathway might allow analgesia with a reduced side effect profile (III-D1.W.08).
