Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model

Abstract

Peripheral neuropathic pain (PNP) resulting from injury or dysfunction to a peripheral nerve, is a major health problem affecting 7–8% of the population. It is inadequately controlled by current drugs, and is characterized by pain hypersensitivity which is believed to be due to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: a) whether reducing levels of nitric oxide (NO), with 1400 W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent/attenuate pain hypersensitivity, and b) the effects of 1400 W on plasma levels of several cytokines that are secreted post iNOS upregulation during chronic pain states. The L5-spinal nerve axotomy (SNA) model of PNP was used, and 1400 W (20 mg kg⁻¹) administered intraperitoneally at 8 hour intervals for three days starting at 18 hours post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400 W were examined using multiplex ELISA. SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400 W significantly: (a) limited development of mechanical hypersensitivity at 66 hours post-SNA, as well as heat hypersensitivity at 42 hours and at several time-points tested thereafter, and (b) increased the plasma concentrations of IL-1α, IL-1β, and IL-10 in the SNA rats. The findings suggest that 1400 W may exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1β and IL-1α) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes may be effective for the treatment of PNP.

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