An antagonist of substance P N-terminal fragments, D-substance P(1-7), reveals that both nociceptive and antinociceptive effects are induced by substance P N-terminal activity during noxious chemical stimulation

Substance P (SP) N-terminal fragments are known to alter nociception when injected intrathecally or when released in response to capsaicin. However, it is not known whether a sufficient concentration of SP N-terminal metabolites accumulate during noxious stimulation to modulate nociception. To test this, we examined the effect of the SP(1-7) antagonist, D-SP(1-7), injected intrathecally in mice, on two nociceptive assays that are differentially affected by exogenous SP(1-7): acetic acid-induced writhing that is inhibited and formalin-induced behaviors that are enhanced by SP(1- 7). One nmol of D-SP(1-7) is sufficient to block the acute (30 min) antinociceptive effects of SP(1-7) on writhing. When injected alone at much higher doses (10-100 nmol), D-SP(1-7) inhibited writhing. In the formalin assay, SP(1-7) had no acute effect (30 min) on responses during Phase 1 at any dose tested, but D-SP(1-7) increased responses 5 min after injection of low (2-1000 pmol), but not high doses (10 and 100 nmol). Twenty-four hours after injection of SP(1-7), writhing was inhibited and formalin responses were increased. D-SP(1-7) prevented these effects of SP(1-7) but had no effect when injected alone, indicating that there is no tonic SP N-terminal activity in mice not exposed to noxious stimuli. Thus, acetic acid and formalin each induce endogenous SP N-terminal activity, respectively, producing a pro-nociceptive effect that is relatively insensitive to D-SP(1- 7) and antinociception that is very sensitive to inhibition by D-SP(1-7).