Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Full length article Inhibition of the potassium channel K Ca 3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury Roland G.W. Staal a, ⁎ , Tanzilya Khayrullina a , Hong Zhang a , Scott Davis b , Shaun M. Fallon a , Manuel Cajina c , Megan E. Nattini c , Andrew Hu b , Hua Zhou c , Suresh Babu Poda c , Stevin Zorn a , Gamini Chandrasena c , Elena Dale a , Brian Cambpell a , Lars Christian Biilmann Rønn d , Gordon Munro d , Thomas Mӧller a a Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA b Psychogenics Inc., 765 Old Saw Mill River Rd #104, Tarrytown, NY 10591, USA c Molecular Pharmacology, Bioanalysis & Operations, Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652, USA d Neurodegeneration Disease Biology Unit, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark ARTICLE INFO Chemical compounds: Senicapoc ICA-17043 Gabapentin Keywords: Neuropathic pain Chronic constriction injury K Ca 3.1 KCNN4 Calcium-activated potassium channel Tactile allodynia Von Frey Microglia ICA-17043 Senicapoc ABSTRACT Neuropathic pain is a debilitating, chronic condition with a significant unmet need for effective treatment options. Recent studies have demonstrated that in addition to neurons, non-neuronal cells such as microglia contribute to the initiation and maintenance of allodynia in rodent models of neuropathic pain. The Ca 2+ - activated K + channel, K Ca 3.1 is critical for the activation of immune cells, including the CNS-resident microglia. In order to evaluate the role of K Ca 3.1 in the maintenance of mechanical allodynia following peripheral nerve injury, we used senicapoc, a stable and highly potent K Ca 3.1 inhibitor. In primary cultured microglia, senicapoc inhibited microglial nitric oxide and IL-1β release. In vivo, senicapoc showed high CNS penetrance and when administered to rats with peripheral nerve injury, it significantly reversed tactile allodynia similar to the standard of care, gabapentin. In contrast to gabapentin, senicapoc achieved efficacy without any overt impact on locomotor activity. Together, the data demonstrate that the K Ca 3.1 inhibitor senicapoc is effective at reducing mechanical hypersensitivity in a rodent model of peripheral nerve injury. 1. Introduction Existing treatments for neuropathic pain provide effective relief to only 1 in 4 patients (Attal et al., 2010; Finnerup et al., 2015). The majority of these treatments are aimed at targets expressed by neurons of the somatosensory system (e.g. opioid receptors and α2δ subunit of calcium channels). Expression of these targets in other areas of the CNS are believed to underlie their propensity to cause side effects such as sedation, euphoria and addiction (Finnerup et al., 2015). Recent studies have shown that non-neuronal targets expressed by activated immune cells also contribute to the establishment and maintenance of tactile allodynia in rodent models of neuropathic pain (Ren and Dubner, 2010; Scholz and Woolf, 2007; Zhuo et al., 2011). The clinical relevance of these findings was demonstrated by a recent PET study that showed an increase in PBR28 binding in the thalamus of patients with chronic back pain (Loggia et al., 2015). PBR28 is a ligand for the translocator protein (TSPO) that increased expression in activated microglia, the CNS resident immune cells (Rupprecht et al., 2010). Collectively, the studies suggest that microglial activation may be a mechanism common to neuropathic pain models as well as patients with chronic or neuropathic pain. Targeting microglia might provide novel therapeutic options for patients with these debilitating diseases. Mechanistically, immune cell receptor activation results in eleva- tions of intracellular Ca 2+ concentrations which can subsequently stimulate diverse physiological responses including migration, prolif- eration, phagocytosis as well as production and release of cytokines, chemokines, prostanoids and reactive oxygen and nitrogen species (Hanisch, 2013). Many studies in models of neuropathic pain have demonstrated that inhibition of these immune cell receptors in the CNS (presumably on microglia) blocks the physiological sequelae of immune http://dx.doi.org/10.1016/j.ejphar.2016.11.031 Received 6 April 2016; Received in revised form 18 November 2016; Accepted 18 November 2016 ⁎ Correspondence to: 215 College Rd #100, Paramus, NJ 07652 USA. E-mail address: staalro@yahoo.com (R.G.W. Staal). European Journal of Pharmacology 795 (2017) 1–7 0014-2999/ © 2016 Elsevier B.V. All rights reserved. Available online 19 November 2016 crossmark