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Eur J Pharmacol. 2017 Jan 15;795:1-7. doi: 10.1016/j.ejphar.2016.11.031. Epub 2016 Nov 19.

Inhibition of the potassium channel KCa3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury.

Author information

1
Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA. Electronic address: staalro@yahoo.com.
2
Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ 07652, USA.
3
Psychogenics Inc., 765 Old Saw Mill River Rd #104, Tarrytown, NY 10591, USA.
4
Molecular Pharmacology, Bioanalysis & Operations, Lundbeck Research USA Inc., 215 College Road, Paramus, NJ 07652, USA.
5
Neurodegeneration Disease Biology Unit, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.

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 Ca2+- activated K+ channel, KCa3.1 is critical for the activation of immune cells, including the CNS-resident microglia. In order to evaluate the role of KCa3.1 in the maintenance of mechanical allodynia following peripheral nerve injury, we used senicapoc, a stable and highly potent KCa3.1 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 KCa3.1 inhibitor senicapoc is effective at reducing mechanical hypersensitivity in a rodent model of peripheral nerve injury.

KEYWORDS:

Calcium-activated potassium channel; Chronic constriction injury; Gabapentin; ICA-17043; K(Ca)3.1; KCNN4; Microglia; Neuropathic pain; Senicapoc; Tactile allodynia; Von Frey

PMID:
27876619
DOI:
10.1016/j.ejphar.2016.11.031
[Indexed for MEDLINE]

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