After exposure of tilapia for 7 days to low-pH water, plasma thyrotropin-releasing hormone (TRH) levels were elevated, and the melanocyte-stimulating hormone (MSH) cells in the pituitary pars intermedia had increased in size and showed enhanced synthetic and secretory activity. The MSH cells became more sensitive to TRH but not to corticotropin-releasing hormone (CRH). Stimulation by TRH (but not by CRH) of the MSH cells of tilapia exposed to low pH specifically enhanced the release of diacetyl alpha-MSH, the most potent corticotropic form of alpha-MSH. Acute stress imposed by handling and confinement for 1 h elevated the plasma cortisol level but did not affect blood plasma alpha-MSH levels. We conclude that stimulation by TRH is pivotal for an enhanced release of diacetyl alpha-MSH during low-pH adaptation. These results are further evidence of a role for TRH and alpha-MSH in the activation of the hypothalamopituitary-interrenal axis during adaptation to low pH.