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

GONZÁLEZ S; LABOMBARDA F; CORONEL F; DE NICOLA A; VILLAR M

Washington, USA

Congreso; 38th Annual Meeting of the Society for Neuroscience; 2008

Society for Neuroscience

&amp;lt;!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";} h1 {mso-style-next:Normal; margin:0cm; margin-bottom:.0001pt; mso-pagination:none; page-break-after:avoid; mso-outline-level:1; font-size:16.0pt; mso-bidi-font-size:10.0pt; font-family:"Courier New"; mso-bidi-font-family:"Times New Roman"; mso-font-kerning:0pt; mso-fareast-language:ES; layout-grid-mode:line; mso-bidi-font-weight:normal;} p.MsoPlainText, li.MsoPlainText, div.MsoPlainText {margin:0cm; margin-bottom:.0001pt; mso-pagination:none; font-size:10.0pt; font-family:"Courier New"; mso-fareast-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman"; mso-ansi-language:ES; mso-fareast-language:ES; layout-grid-mode:line;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --&amp;gt;Central neuropathic pain 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 well-recognized model of central neuropathic pain to study the effects of PROG administration on the expression of NMDA receptor (NMDAR), preprodynorphin (ppD) and protein kinase C gamma (PKCgama), critical players in nociceptive processing at the spinal level. Sprague-Dawley 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 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 NMDAR subunits (NR1, NR2A and NR2B), ppD, PKCgama and the housekeeping gene cyclophilin A in the dorsal horn caudal to the injury site. 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 (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 PKCgama (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 animals (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 PKCgama 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 central neuropathic pain, 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