Ultra-low doses (fmoles/min) of methionine-enkephalin-arginine-phenylalanine (MEAP) improve vagal transmission (vagotonic) and decrease heart rate by stimulating ₁-opioid receptors within the sinoatrial (SA) node. Higher doses of MEAP (nmoles/min) acting on ₂-opioid receptors interrupt vagal transmission (vagolytic) and reduce the decline in heart rate. Preconditioning-like occlusion of the nodal artery produced a vagotonic response that was reversed by the ₁-receptor antagonist BNTX. This study was designed to test the hypothesis that extended ₁-opioid receptor stimulation reduces ₂-opioid receptor responses. The vagi were isolated, ligated and the right vagus was stimulated to produce a two-step decline in heart rate. In study one, the ₂-agonist, deltorphin II was introduced into the SA node by microdialysis to evaluate the ₂-response before and after the infusion of the ₁-agonist, TAN-67. TAN-67 reduced the vagolytic effect of deltorphin by two thirds. In study two, the selective 1-antagonist BNTX was combined with TAN-67. BNTX preserved the deltorphin response suggesting that attrition of the prior response was mediated by ₁-receptor activity. When TAN 67 was omitted in time control studies, some loss of the ₂-response was apparent in the absence of the 1-agonist. This loss was also eliminated by the ₁-antagonist, BNTX suggesting that the attenuation following deltorphin was also due to ₁-activity. Additional studies were conducted to determine the effect of TAN-67 in the absence of prior deltorphin. When time controls were conducted without the initial deltorphin treatment a robust vagolytic response was observed. When this same deltorphin was preceded by TAN 67, the vagolytic response was significantly eroded. BNTX infused after loss of the ₂-response was unable to reverse the loss. These data support the conclusion that the loss of the ₂-response resulted from reduced ₂-activity mediated by continued ₁-receptor stimulation and not the arithmetic consequence of increased competition from that same ₁-activity