Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin‐releasing factor‐induced inhibition of gastric acid secretion in rats

1 The central interactions between the sigma ligand, JO 1784, [(+)‐N‐cylcopropylmethyl‐N‐methyl‐1,4‐diphenyl‐1‐ethylbut‐3‐en‐1‐ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin‐releasing factor (CRF)‐induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 μg kg−1 h−1, i.v.) stimulated conditions. 2 Intracisternal injection of CRF (10 μg), bombesin (0.1 μg) and human recombinant interleukin‐1β (hIL‐1β, 0.1 μg) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 μg) or JO 1784 (0.5 μg) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose‐related (0.01–0.5 μg) and peptide‐specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL‐1β. 3 The putative sigma receptor antagonist, BMY 14802, (1 mg kg−1, s.c.) did not influence pentagastrin‐stimulated acid secretion nor CRF‐induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4 CRF (3 μg) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin‐stimulated gastric acid secretion by 61% and 51%; NPY (0.03 μg) or JO 1784 (0.03 μg) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action. Microinjection into the LH had no effect. 5 In conclusion, NPY and JO 1784 (a sigma ligand) interacts with CRF in the PVN to block CRF‐induced inhibition of pentagastrin‐stimulated gastric acid secretion. The central action of JO 1784 and NPY is specific to CRF and may involve sigma binding sites.