Morphine sulfate (MS) and pentobarbital (PB) stimulate growth hormone (GH) release in the rat in vivo, but not from enzymatically dissociated anterior pituitary cells in vitro. Somatostatin and thyrotropin-releasing factor (TRF) inhibit the in vivo release of GH induced by MS, with 50% inhibition at ca. 2.3 and 4.6 mug/100 g BW, respectively. Somatostatin and TRF similarly inhibit PB-induced GH release. Prostaglandin E2 stimulates GH release both in vivo and in vitro. Both of these responses are inhibited by somatostatin (50% inhibition at ca. 10 mug/100g BW), but neither is altered by TRF (100 mug/100g BW). Both normal and hypophysectomized rats receiving MS exhibited a rapid vibration of the tail immediately after administration of TRF (30 mug/100g BW). Structural analogs of TRF with low TSH-releasing activity did not inhibit GH release nor induced tail vibration in MS-treated rats. Pyroglutamyl-3-methyl-histidyl-prolinamide, with 8 times the hypophysiotropic potency of TRF, is similarly more potent than TRF in inhibiting GH release and inducing tail vibration in MS-treated rats. These results suggest the following: 1) MS and PB act at a central nervous system (CNS) site to release GH; 2) TRF may act at a CNS site to inhibit MS- and PB-induced GH release; 3) somatostatin has direct pituitary effects on inhibition of GH, but a CNS site of action cannot be excluded; and 4) TRF stimulates tail motor activity in MS-treated rats.