Intracisternal antisense oligonucleotides to TRH receptor abolish TRH-evoked gastric motor excitation.

Thyrotropin-releasing hormone (TRH) from the nucleus raphe obscurus (nROb) innervates the dorsal vagal complex (DVC) and activates gastric motor function. Assessment of the importance of TRH has been hampered by the lack of TRH receptor antagonists. To overcome this, rats were given intracisternal antisense oligonucleotides against the first 18 bases of TRH receptor mRNA, mismatch oligonucleotides, or saline. Rats were anesthetized, and L-glutamate (15 nmol), TRH (1 and 10 pmol), and saline were microinjected into the DVC and nROb while gastric motor function was monitored. Intracisternal TRH mRNA antisense oligonucleotides abolished the gastric excitatory affects of microinjection of TRH, but not L-glutamate, into the DVC, and the response to TRH recovered after 2 wk of no antisense treatment. Chemical stimulation of the nROb increased intragastric pressure in saline- and mismatch- but not antisense-treated animals. These studies demonstrate that intracisternal TRH receptor antisense oligonucleotides produce a selective and reversible "knockdown" of responsiveness to exogenous TRH in the DVC, as well as to excitation of an endogenous TRH pathway controlling gastric function. It also provides a new tool for assessment of TRH pathways in hindbrain control of gastric function.