The autoregulation of the histamine release via the histamine H3 receptor in the periphery was studied in vivo and in vitro. Antidromic electrical stimulation of the sciatic nerve caused a significant increase in histamine release in the subcutaneous perfusate in the rat hindpaw. (R)alpha-methylhistamine, a specific H3 receptor agonist, significantly and dose-dependently inhibited the increase in release of histamine by antidromic stimulation at intravenous doses of 0.25-2 mg/kg. Thioperamide (2 mg/kg, intraperitoneally), a specific H3 antagonist, prevented the inhibitory effect of (R)alpha-methylhistamine. Substance P perfusion (5-50 microM) also elicited a significant increase in histamine, and a significant inhibition by (R)alpha-methylhistamine and the antagonism of thioperamide were observed. (R)alpha-methylhistamine inhibited the histamine release by substance P from rat peritoneal mast cells in vitro, and thioperamide reduced the response to (R)alpha-methylhistamine. These data suggest that mast cells may have histamine H3 receptors, and that histamine probably modulates its own release through the H3 receptor in neurogenic inflammation.