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

1 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. 2 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. 3 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). 4 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). 5 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.). 6 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. 7 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. 8 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.British Journal of Pharmacology (1998) 125 , 87–101; doi: 10.1038/sj.bjp.0702053