BMY 7378: Partial agonist at spinal cord 5-HT(1A) receptors

Recent data indicate that BMY 7378 demonstrates high affinity, selectivity and low intrinsic activity at hippocampal 5-HT(1A) receptors, suggesting that BMY 7378 may represent the first selective 5-HT(1A) functional antagonist. The present study examined the agonist and antagonist properties of BMY 7378 at spinal cord 5-HT(1A) receptors. In electrophysiological studies, iontophoretic administration of either the 5-HT(1A) agonist 8-OH-DPAT (43.8 +/- 5.4 nA) or BMY 7378 (46.3 +/- 5.2 nA) significantly inhibited the firing rate of wide-dynamic-range dorsal horn units indicating that BMY 7378 demonstrates significant intrinsic activity at spinal cord 5-HT(1A) receptors. Concomitant BMY 7378 and 8-OH-DPAT administration identified no BMY 7378 ejection current (20-100 nA) which antagonized the 8-OH-DPAT induced inhibition of dorsal horn unit activity. In behavioral studies in the spinal rat, 8-OH-DPAT increased the animals' sensitivity to noxious levels of mechanical stimulation (ED(50) = 269 +/- 24 nmol/kg) as did BMY 7378 (ED(50) = 295 +/- 70 nmol/kg) with no statistically significant difference in the maximal response (Y(max)) observed. Concomitant BMY 7378 and 8-OH-DPAT administration identified no BMY 7378 dose (10-1100 nmol/kg) which blocked the hyperalgesic effect of 8-OH-DPAT, rather, each drug produced similar effects which were additive. Further, the 5-HT(1A) agonist effects of BMY 7378 were blocked by the 5-HT(1A) antagonist, spiperone. Therefore, both the electrophysiologic and reflex data indicate that BMY 7378 possesses significant intrinsic activity at spinal cord 5-HT(1A) receptors, and like 8-OH-DPAT is a partial agonist at these receptors. Differences in BMY 7378 intrinsic activity at spinal cord as opposed to hippocampal 5-HT(1A) receptors are discussed in terms of regional differences in G-proteins coupled to 5-HT(1A) receptors in these two CNS regions.