Capsaicin, the primary pungent component of hot peppers, produced chemogenic and thermal antinociception within two hours after administration to adult guinea pigs (2-8 mg/kg). Antinociception lasted in excess of 10 days. In addition, in somewhat higher doses (4-25 mg/kg s.c.) capsaicin also depleted the putative peptide neurotransmitter, substance P, from primary afferent neurons. Depletion of substance P by capsaicin did not occur until at least one day after capsaicin treatment and the onset of antinociception. Antinociception produced by capsaicin appeared to be a result of bioactivation and covalent binding of capsaicin to the distal ends of sensory neurons. Capsaicin depleted substance P from sensory nerves by inhibiting the rate of substance P synthesis by 48 percent. Inhibition of substance P synthesis by capsaicin occurred with some degree of specificity as the rate at which total protein was synthesized was unchanged. The biochemical mechanism by which capsaicin altered substance P synthesis involved alterations in the retrograde axoplasmic transport of nerve growth factor. Doses of capsaicin which depleted substance P also inhibited the retrograde axoplasmic transport of nerve growth factor. Inhibition of the retrograde transport of nerve growth factor by capsaicin preceded substance P depletion. Supplementation of guinea pigs with mouse nerve growth factor completely prevented capsaicin-induced substance P depletion. It is concluded that capsaicin depletes substance P from primary afferent neurons of the adult guinea pig by altering the availability of NGF. The data support a role for NGF in the normal maintenance of neuropeptide levels in some sensory neurons in the adult animal.