Peripheral and/or central effects of racemic- S(+)- and R(−)-flurbiprofen on inflammatory nociceptive processes: a c-Fos protein study in the rat spinal cord

摘要

class="enumerated" style="list-style-type:decimal">We have evaluated the effects of intravenous or intraplantar racemic-, S(+)- and R(−)-flurbiprofen on both the carrageenan-evoked peripheral oedema and spinal c-Fos immunoreactivity, an indirect index of neurons involved in spinal nociceptive processes.Three hours after intraplantar injection of carrageenan (6 mg in 150 μl of saline) in awake rats, a peripheral oedema and numerous c-Fos protein-like immunoreactive (c-Fos-LI) neurons in L4–L5 segments were observed. c-Fos-LI neurons were essentially located in the superficial (I–II) and deep (V–VI) laminae of the dorsal horn.Intravenous racemic-flurbiprofen (0.3, 3 and 9  mg kg⁻¹) dose-relatedly reduced the carrageenan-evoked oedema and spinal c-Fos expression (r=0.64, r=0.88 and r=0.84 for paw diameter, ankle diameter and number of c-Fos-LI neurons; P<0.05, P<0.001 and P<0.001 respectively).Similar effects to those of intravenous racemic-flurbiprofen were obtained with intravenous S(+)-flurbiprofen (0.3, 3 and 9 mg kg⁻¹) which dose-relatedly reduced the number of c-Fos-LI neurons (r=0.69, P<0.01) and diameters of paw and ankle (r=0.56 and r=0.52 respectively, P<0.05 for both).For the dose of 0.3 mg kg⁻¹ i.v., R(−)-flurbiprofen did not modify the number of c-Fos-LI neurons and produced a weak reduction of oedema at only the ankle level (23±12% reduction, P<0.05). However, a ten times higher dose of R(−)-flurbiprofen (3 mg kg⁻¹ i.v.) was necessary to obtain effects comparable to those of S(+)- or racemic-flurbiprofen (0.3 mg kg⁻¹ i.v.).Intraplantar racemic-flurbiprofen (1, 10 and 30 μg) dose-relatedly reduced the carrageenan-enhanced ankle diameter (r=0.81, P<0.001) and the number of c-Fos-LI neurons in L4–L5 segments (r=0.83, P<0.001), with a 60±3% reduction of the number of c-Fos-LI neurons (P<0.001), and 30±3 and 67±7% reduction of paw and ankle diameter respectively (P<0.001 for both) for the dose of 30 μg.For intraplantar S(+)-flurbiprofen (1, 10 and 30  μg) the dose-related effects (r=0.77, r=0.60 and r=0.59 for c-Fos-LI neurons, paw and ankle diameters respectively, P<0.001, P<0.01 and P<0.01) were similar to those of racemic-flurbiprofen. In contrast, intraplantar R(−)-flurbiprofen (1, 10 and 30 μg) did not have detectable effects on all studied parameters.The present study provides clear evidence for potent anti-inflammatory and antinociceptive effects of both intravenous or intraplantar racemic- and S(+)-flurbiprofen. These results further demonstrate marked anti-inflammatory and antinociceptive effects of intravenous, but not intraplantar, R(−)-flurbiprofen. These results suggest that the main site of action of racemic- and S(+)-flurbiprofen is in the periphery and indicate that the site of action of R(−)-flurbiprofen is mainly of central origin.