ORIGINAL ARTICLE Progesterone reduces the expression of spinal cyclooxygenase-2 and inducible nitric oxide synthase and prevents allodynia in a rat model of central neuropathic pain M.F. Coronel 1 *, F. Labombarda 2,3 *, A.F. De Nicola 2,3 , S.L. González 1,3 1 Laboratorio de Nocicepción y Dolor Neuropático, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina 2 Laboratorio de Bioquímica Neuroendócrina, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina 3 Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Argentina Correspondence Susana Laura González E-mail: sugnzlz@gmail.com *Both authors equally contributed to this work and therefore should be regarded as joint first authors Funding sources This work was supported by Universidad de Buenos Aires (Grant no. 20020090200126), CONICET (PIP 201-101-00576) and Fundación Alberto J. Roemmers. Conflicts of interest None declared. Accepted for publication 26 June 2013 doi:10.1002/j.1532-2149.2013.00376.x Abstract Background: Spinal cord injury (SCI) results in the development of chronic pain that is refractory to conventional treatment. Progesterone, a neuroprotective steroid, may offer a promising perspective in pain modulation after central injury. Here, we explore the impact of progesterone administration on the post-injury inflammatory cascade involving the enzymes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) at the spinal cord level. We also analyse pain behaviours, the profile of glial cell activation, and IκB-α mRNA levels, as an index of NF-κB transactivation. Methods: We used biochemical, immunohistochemical and molecular techniques, as well as behavioural studies, to investigate the effects of progesterone in a well-characterized model of central neuropathic pain. Results: Injured animals receiving progesterone presented reduced mRNA levels of the proinflammatory enzymes, as well as decreased COX-2 activity and nitrite levels, as compared to vehicle-treated injured rats. Further, animals receiving the steroid exhibited lower levels of IκB-α mRNA, suggesting decreased NF-κB transactivation. Progesterone administration also attenuated the injury-induced increase in the number of glial fibrillary acidic protein and OX-42 positive cells both at early and late time points after injury, and prevented the development of mechanical and thermal allodynia. Further, when injured rats received early progesterone administration for a critical period of time after injury, they did not display allodynic behaviours even after the treatment had stopped. Conclusions: Our results suggest that progesterone, by modulating early neuroinflammatory events triggered after SCI, may represent a useful strategy to prevent the development of central chronic pain. 1. Introduction Chronic pain develops in nearly 70% of patients with spinal cord injury (SCI) with a significant impact on functioning, mood and life satisfaction. Unfortunately, currently available pharmacotherapy has limited effi- cacy and adverse side effects (Finnerup and Baastrup, 2012). SCI evokes a complex cascade of events with initial mechanical damage leading to secondary injury that proceeds through the spinal release of mediators like cytokines, reactive oxygen species, prostaglandins and nitric oxide (NO), all of which contribute to functional impairment and chronic pain (Yezierski, 2009). Cyclooxygenase (COX), the enzyme responsible for the synthesis of prostaglandins, is known to have two © 2013 European Pain Federation - EFIC ® 348 Eur J Pain 18 (2014) 348–359