In vivo signal transduction of tetrodotoxin-sensitive nociceptive responses by substance P given into the planta of the mouse hind limb.

1. We developed a simple and sensitive peripheral analgesic test in mice. 2. Substance P (SP) given into the planta (i.pl.) of the mouse hind limb produced a flexor response. The flexor response was dependent on SP doses (0.1-100 pmol, i.pl.). When SP (10 pmol) was given every 5 min, there were stable flexor responses. These nociceptive responses were completely abolished by CP-96,345, a neurokinin 1 receptor antagonist. 3. SP-induced responses were also blocked by several signal transduction-related compounds, such as tetrodotoxin, EGTA, and U73122, a selective phospholipase C inhibitor. 4. These findings suggest that SP depolarizes peripheral nerve endings, possibly through inositol trisphosphate (Ins P3)-gated Ca2+ influx, followed by induction of action potentials in the peripheral axons of primary afferent neurons.