Mutual antagonism between nerve growth factor and substance P N-terminal activity on nociceptive activity in mice

Nerve growth factor (NGF) induces a relatively long-term hyperalgesia in rats, whereas substance P (SP) N-terminal fragments, like SP(1-7), produce a long-lasting antinociception in mice. We used various nociceptive assays to compare the effects of these compounds on pain transmission when injected intrathecally (i.t.) in mice, and to determine whether either compound affects the action of the other. NGF produced thermal hyperalgesia when injected i.t. in mice 24 and 48 hr before testing by the tail-flick assay. During this same interval, NGF elicited no effect on the response to von Frey fibers or on chemically induced nociception measured by the writhing assay. In contrast to NGF, SP(1-7) had no effect on tail-flick latencies but induced antinociception in the writhing assay 24 hr after injection. When administered 2 hr before NGF, SP(1-7) antagonized the thermal hyperalgesic effect of NGF in a dose-related fashion, despite the inability of SP(1-7) to alter tail-flick latency when administered alone. NGF, in turn, antagonized the antinociceptive effects of SP(1-7) in the writhing assay. The D-amino acid-substituted analog, D-SP(1-7), failed to mimic the antinociceptive effect of SP(1-7) or to alter the hyperalgesic effect of NGF, which indicated a stereoselective action of SP(1-7). D-SP(1-7), that inhibits SP(1-7) binding, did reverse the ability of SP(1-7) to antagonize NGF-induced hyperalgesia, consistent with its action as a SP N-terminal antagonist. Mutual antagonism between NGF and SP may reflect modulatory roles of these endogenously occurring peptides during chronic pain when N-terminal metabolites of SP may accumulate.