In the rat carrageenan model of inflammation, systemically administered CRF significantly reduced hyperalgesia, edema and hyperthermia. While hypophysectomy had no effect, adrenalectomy blocked the effects of systemic CRF on edema and hyperthermia, and tended to reduce the peptide's ability to suppress hyperalgesia. When CRF was injected into one of two bilaterally inflamed hindpaws, it significantly inhibited hyperalgesia via a peripheral mechanism. In this model of inflammation, the antinociceptive effects of CRF are peripherally mediated, while the anti-inflammatory effects are dependent on the adrenal gland.