PHYSIOLOGICAL CONTRIBUTIONS OF NEUROKININ-1 RECEPTOR ACTIVATION, AND INTERACTIONS WITH NMDA RECEPTORS, TO INFLAMMATORY-EVOKED SPINAL C-FOS EXPRESSION

1. Intraplantar injection of formalin (5%, 100 mu l in saline) was ass ociated with a high level of spinal c-Fos immunoreactivity and a perip heral paw and ankle edema, as assessed at 3 h after formalin administr ation. For the two experimental series, the control number of formalin -evoked Fos-like immunoreactive (Fos-LI) neurons were 174 +/- 6 and 19 3 +/- 18 (means +/- SE) Fos-LI neurons per 40-mu m section of the lumb ar segment L4-L5 of the rat spinal cord. For both series of experiment s, Fos-LI neurons were located predominantly in the superficial (I-II; 40 and 44% of the total number of Fos-LI neurons for the two experime ntal series) and deep (V-VI: 37 and 40% of the total number of Fos-LI neurons for the two experimental series) laminae of the dorsal horn of the spinal cord. The small number of remaining Fos-LI neurons were lo cated in the nucleus proprius (laminae III-IV) and the ventral horn. 2 . Prior intravenous administration of RP67580 (0.05, 0.5, and 1.5 mg/k g), a selective neurokinin I (NK1) receptor antagonist, dose-relatedly reduced the total number of formalin evoked Fos-LI neurons (88 +/- 5% , 80 +/- 4%, P < 0.01 and 64 +/- 4%, P < 0.0001, of the control number of formalin-evoked Fos-LI neurons). Laminar analysis of the regional effect of RP67580 on formalin-evoked Fos-LI neurons illustrated that t he number of superficial and deep laminae Fos-LI neurons were attenuat ed to a similar extent by RP67580. 3. Prior intravenous administration of RP68651 (1.5 mg/kg), the inactive isomer of RP67580, produced only a small reduction in the total number of formalin-evoked Fos-LI neuro ns (84 +/- 5% of the control number of formalin-evoked Fos-LI neurons, P < 0.05). The effect of RP68651 on the number of formalin-evoked Fos -LI neurons was significantly smaller (P < 0.01) than the effect of th e equivalent concentration of RP67580, the active isomer. 4. Prior coa dministration of intravenous RP67580 (0.5 mg/kg) and subcutaneous (+)- HA966 (2.5 mg/kg), an antagonist at the glycine site of the N-methyl-D -aspartate (NMDA) receptor, significantly reduced the number of formal in-evoked Fos-LI neurons (63 +/- 4% of the control number of formalin- evoked Fos-LI neurons, P < 0.01). The attenuating effect of coadminist ered RP67580 and (+)-HA966 was significantly greater than the effect o f RP67580 alone (P < 0.01) and the effect of (+)-HA966 alone (P < 0.05 ). Laminar analysis illustrated that coadministered RP67580 and (+)-HA 966 reduced the number of formalin-evoked Fos-LI neurons in the superf icial and deep laminae to a similar extent. 5. Intraplantar injection of formalin was associated with a peripheral paw (0.92 +/- 0.02 cm) an d ankle (0.92 +/- 0.02 cm) edema, as compared with the paw (0.46 +/- 0 .02 cm) and ankle (0.67 +/- 0.14 cm) diameters of saline-stimulated ra ts. Neither prior administration of intravenous RP67580 (0.05, 0.5, an d 1.5 mg/kg) or RP68651 (1.5 mg/kg) or prior coadministration of RP675 80 (0.5 mg/kg) and (+)-HA966 (2.5 mg/kg) influenced the extent of the paw or ankle edema at 3 h after intraplantar injection of formalin. 6. Our results illustrate that NK1-receptor activation contributes to in flammatory-evoked spinal c-Fos expression and thus supports the curren t contention that NK1-receptor activation, and by inference SP, plays a role in spinal nociceptive processing. The second part of our study suggests that the previously reported NK1/NMDA-receptor interactions c ontribute to formalin-evoked spinal c-Fos expression and consequently may contribute to the longer term spinal neuroplasticity associated wi th inflammatory nociceptive processing.