Progesterone modulates spinal cytokine expression profile and prevents neuropathic pain after spinal cord injury

GONZALEZ, SL; LABOMBARDA F; CORONEL MF; DE NICOLA AF; VILLAR MJ

Montreal, Canadá

Congreso; XIII World Congress on Pain; 2010

International Association for the Study of Pain

Spinal cord injury (SCI) results in the development of chronic pain that is refractory to conventional treatment. Glial cell activation and the consequent production of inflammatory cytokines contribute to the pathology of central neuropathic syndromes and represent a therapeutic target. We have previously reported that progesterone (PROG), a neuroprotective steroid, may offer a promising perspective in pain modulation. In the present study, we used a model of central pain to evaluate the effects of PROG on the temporal profile expression of interleukine-1 beta (IL-1b) and its receptors (IL-1 R1 and IL-1 R2), IL-6, tumor necrosis factor-alpha (TNF-a), cyclooxigenase-2 (COX-2) and the inducible nitric oxide synthase (iNOS), all key players in nociceptive processing at the spinal level. Sprague-Dawley male rats subjected to spinal hemisection at T13 level received daily subcutaneous injections of PROG (Hx+PROG; 16 mg/kg) or vehicle (Hx). Uninjured rats were used as control animals (CTL). Mechanical and thermal allodynia of the hindpaws were assessed with the von Frey and Choi tests respectively. Real-time PCR was employed to determine the relative mRNA levels of the inflammatory cytokines and their receptors, COX-2 and iNOS and the housekeeping gene cyclophilin A in the dorsal horn caudal to the injury site. One day after SCI, a significant increase in the mRNAs levels for IL-1b, IL1-R2, IL-6, TNF-a, COX-2 and iNOS was observed (results are expressed as fold-increase relative to CTL levels:  IL-1 b: 4.300±0.946, p<0.001; IL-1 R2: 5.875±1.430, p<0.001; IL-6: 6.109±1.439, p<0.01; TNF-a: 14.140±1.498, p<0.001; COX-2: 8.547±1.130, p<0.001, and iNOS: 7.618±1.355, p<0.001 vs CTL in all cases). No differences were detected in IL-1 R1 expression. Thirty days after injury, Hx rats showed well-established mechanical and thermal allodynic responses and a significant 2-fold increase in the relative IL-1 R1 mRNA (p<0.01 vs CTL) although the mRNA levels for the cytokines remained similar to those observed in CTL animals (p>0.05). In contrast, one day after injury, Hx+PROG animals presented significantly lower levels of mRNAs for the cytokines and the enzymes COX-2 and iNOS as compared to Hx (IL-1b: 1.690±0.485, p<0.001; IL-6: 1.733±0.399, p<0.01; TNF-a: 6.883±1.998, p<0.001; COX-2: 1.566±0.714, p<0.001, and iNOS: 1.324±0.452, p<0.001 vs Hx in all cases). PROG further increased the mRNA levels for the decoy receptor IL-1 R2 (p<0.001 vs Hx) and reduced the observed IL-1 R1 mRNA up-regulation at the chronic time-point (IL-1 R1: 0.842±0.220, p<0.01 vs Hx). Interestingly, Hx+PROG animals did not develop mechanical allodynia and showed reduced sensitivity to cold stimulation. Our results suggest that PROG, by modulating the neuroinflammatory events triggered after SCI, may represent a useful therapeutic strategy to prevent the development of central chronic pain.