Antinociceptive effects of peripheral benzodiazepine receptors.

Pretreatment of mice with Ro5-4864 or PK11195 inhibited the first- and second-phase responses in the formalin test and this effect was significantly reversed by aminoglutethimide, an inhibitor of pregnenolone synthesis, suggesting that the antinociceptive effect of the peripheral-type benzodiazepine receptor ligands is dependent on steroid formation. Doses of Ro5-4864 that did not produce an antinociceptive effect when injected by the intraperitoneal route presented an analgesic effect, if infected by the intracerebroventricular, intrathecal or intraplantar routes. PK11195 pretreatments with intrathecal, intracerebroventricular or intraplantar doses had no effect in the formalin test. These results suggest that the antinociceptive effect of Ro5-4864 reflects the influence of this ligand on steroid production not only in many nonneuronal peripheral tissues but also in the nervous system, while the antinociceptive action of PK11195 may be due to the stimulation of steroid synthesis only in nonnervous tissues.

Involvement of steroids in anti-inflammatory effects of peripheral benzodiazepine receptor ligands.

Mouse paw oedema induced by carrageenan is used to determine if glucocorticoids are involved in the anti-inflammatory effects of peripheral benzodiazepine receptor ligands. The anti-inflammatory responses elicited by i.p. treatment with 1-(2-chlorophenyl)-N-methyl-N (1-methyl-propyl)-3-isoquinoline carboxamide (PK11195) and 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2-H-1, 4-benzodiazepin-2 (Ro5-4864) were reversed by aminoglutethimide, an inhibitor of steroidal synthesis. Intraplantar injection into the ipsilateral paw of Ro5-4864, but not PK11195, inhibited the formation of paw oedema and this effect was reversed by aminoglutethimide. These results suggest that glucocorticoids are involved in the systemic and local anti-inflammatory effects of Ro5-4864 and only in the systemic response to PK11195.

Comparison of two PBR ligands with classical antiinflammatory drugs in LPS-induced arthritis in rats.

The antinociceptive and anti-edematogenic effects of peripheral benzodiazepine receptor (PBR) ligands, Ro5-4864 (7-chloro-5- (4-chlorophenyl)-1,3-dihydro-1-methyl-2-H-1,4-benzodiazepine-2) and PK11195 (1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide), were studied in an experimental model of carrageenan/LPS -induced arthritis in rats. These effects were compared with those of indomethacin and dexamethasone. Both pre and post-treatments with PK11195 were found to be anti-edematogenic and antinociceptive. The lower dose (0.01 mg/kg) exhibited the higher anti-edematogenic effect. On the other hand, the higher dose (0.5 mg/kg) produced antinociception, but with a decreased anti-edematogenic effect. Ro5-4864 produced a negligible antinociception and anti-edematogenic effect as pretreatment, but a pro-edematogenic effect when given as post-treatment. Dexamethasone and indomethacin presented parallel and dose-dependent antinociceptive and anti-edematogenic effects. In conclusion, PK11195 can effectively diminish arthritic nociception and edema elicited by LPS, but probably by mechanisms different from those of dexamethasone or indomethacin. RO5-4864 seemed to have opposite effect on this model.