Progesterone attenuates neuropathic pain-associated behaviors and induces changes in the expression of NMDA receptor subunits, preprodynorphin and PKCã in rats subjected to a spinal cord hemisection

M.F. CORONEL; F. LABOMBARDA; M.J. VILLAR; A. F. DE NICOLA; S. L. GONZALEZ

Buzios, Brasil

Congreso; Congreso IBRO/LARC de Neurociencias de América Latina, Caribe y la Península Ibérica; 2008

Sociedad Argentina de Neurociencias

Central neuropathic pain (CNP) is refractory to conventional treatment and remains a therapeutic challenge. Progesterone (PROG), a neuroprotective steroid, may offer a promising perspective in pain modulation. In this work, we used a model of CNP to study the effects of PROG on the expression of NMDA receptor (NMDAR), preprodynorphin (ppD) and protein kinase C gamma (PKCã), critical players in nociceptive processing at the spinal level. Male rats subjected to spinal hemisection at T13 level (n=10) received daily subcutaneous injections of PROG (Hx+PROG; 16 mg/kg, n=5) or vehicle (Hx; n=5). Uninjured rats (n=5) were used as control animals (CTL). Mechanical and thermal allodynia were assessed with the von Frey and Choi tests. Real-time PCR was employed to determine the relative mRNA levels of NMDAR subunits (NR1, NR2A and NR2B), ppD, PKCã and the housekeeping gene cyclophilin A. Thirty days after lesion, Hx rats showed well-established mechanical and thermal allodynic responses. At this time-point, a significant increase in the mRNAs for all NMDAR subunits was observed in the dorsal horn caudal to the injury (results are expressed as fold-increase relative to CTL levels: NR1: 1.303±0.069; NR2A: 1.667±0.194; NR2B: 2.052±0.200, p<0.05 vs CTL in all cases). In addition, a 2-fold increase in both ppD (p<0.05 vs CTL) and PKCã (p<0.01 vs CTL) mRNAs was observed. Hx+PROG animals did not develop mechanical allodynia and showed reduced sensitivity to cold stimulation. In these animals, the levels of NMDAR subunits mRNAs were decreased as compared to Hx, remaining similar to those observed in CTL (NR1: 0.824±0.126; NR2A: 1.12±0.11; NR2B: 0.987±0.163, p<0.05 vs Hx, p>0.05 vs CTL in all cases). PROG treatment also resulted in lower levels of PKCã expression (p<0.05 vs Hx). However, ppD mRNA levels remained up-regulated (p<0.05 vs CTL). Since dynorphin interaction with the NMDAR has been involved in the mechanisms underlying CNP, PROG administration may reduce allodynia by modulating NMDAR expression, thus favoring the analgesic actions of dynorphin. We suggest that PROG, by targeting spinal mechanisms, may be useful in the treatment of chronic pain states (M808-UBACYT).