Differential Effects of Peptide YY, Neuropeptide Y, and σ Ligands on Neurally Stimulated External Pancreatic Secretion in the Rat

The endocrine peptide YY (PYY) inhibits pancreatic secretion in animals and in man through indirect pathways. Neuropeptide Y (NPY), whose chemical structure is very close, displays similar effects. Recently, σ ligands were shown to produce in vivo several neural pharmacologic effects that seemed indistinguishable from those of NPY. This might occur by interaction with the same (or closely related) receptors or by activation of a common final pathway. The purpose of the present work was to test whether PYY, NPY, and σ agonists also display closely related activities on pancreatic secretion. The σ ligands (+)-N-allyl normetazocine (d-NANM) and di(ortho-tolyl) guanidine (DTG) were used. Pancreatic secretion was stimulated by the centrally acting agent 2-deoxyglucose (2DG) in anesthetized rats. The rats were also administered either an infusion of peptide (PYY: 25–250 pmol/kg/h, NPY: 75–750 pmol/kg/h), continued for 2 h, or a bolus injection of d-NANM (3 mg/kg) or DTG (1 mg/kg). In antagonist experiments, the dopamine and σ antagonist haloperidol (1 mg/kg, i.v.), the adrenoceptor antagonists idazoxan (0.3 mg/kg, s.c.), prazosin (0.5 mg/kg, s.c.), propranolol (1 mg/kg, s.c.) and the opiate receptor antagonist naloxone (1 mg/kg, s.c.) were injected, 5 min before the peptide infusion had begun. Neither PYY nor NPY changed basal pancreatic secretion. PYY and NPY produced a dose-related inhibition of 2DG-stimulated pancreatic secretion. The observed inhibition after 250 pmol/kg/h of PYY was volume, 78% (p < 0.01); bicarbonate, 84% (p < 0.01); protein, 78% (p < 0.01); whereas the physiologically relevant dose of 25 pmol/kg/h induced ∼30% inhibition of these variables. NPY was ∼3 times less potent than PYY. The σ ligands d-NANM and DTG had no effect on basal or 2DG-induced pancreatic secretion. Idazoxan suppressed the PYY-induced inhibition, whereas haloperidol, naloxone, prazosin, and propranolol had no effect. Similarly, idazoxan, but not haloperidol, suppressed NPY-induced inhibition of pancreatic secretion. In addition, PYY (75 pmol/kg/h) did not modify the stimulating effect of acetylcholine, which suggests that changes in pancreatic blood flow were not responsible for the PYY-induced decrease of pancreatic secretion. In conclusion, PYY and NPY inhibit 2DG-stimulated pancreatic secretion through a pathway implicating the activation of α-2 adrenoceptors, but neither α-1 nor β adrenoceptors, opiate receptors, or σ receptors. Since σ ligands have no effect, PYY, NPY, and σ ligands display clearly separated effects on pancreatic secretion in the rat.