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Repeated ₁-opioid receptor stimulation reduces ₂-opioid receptor responses in the SA node

University of North Texas Health Science Center, Fort Worth, Texas

Submitted 2 February 2006 ; accepted in final form 9 June 2006

Ultra-low-dose methionine-enkephalin-arginine-phenylalanine improves vagal transmission (vagotonic) and decreases heart rate via ₁-opioid receptors within the sinoatrial (SA) node. Higher doses activate ₂-opioid receptors, interrupt vagal transmission (vagolytic), and reduce the bradycardia. Preconditioning-like occlusion of the nodal artery produced a vagotonic response that was reversed by the ₁-antagonist 7-benzylidenaltrexone (BNTX). The following study tested the hypothesis that extended ₁-opioid receptor stimulation reduces subsequent ₂-receptor responses. The ₂-agonist deltorphin II was introduced in the SA node by microdialysis to evaluate ₂ responses before and after infusion of the ₁-agonist TAN-67. TAN-67 reduced the vagolytic effect of deltorphin by two-thirds. When the ₁-antagonist BNTX was combined with TAN-67, the deltorphin response was preserved, suggesting that attrition of the prior response was mediated by ₁ activity. When TAN-67 was omitted in time control studies, some loss of ₂ responses was apparent in the absence of the ₁ treatment. This loss was also eliminated by BNTX, suggesting that the attenuation of the response after deltorphin alone was also the result of ₁ activity. Additional studies tested TAN-67 alone in the absence of prior deltorphin. When time controls were conducted without the initial deltorphin treatment, a robust vagolytic response was observed. When TAN-67 preceded the delayed deltorphin, the vagolytic response was eroded, indicating an independent effect of TAN-67. BNTX infused afterward was unable to restore the ₂ response. 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 receptor.

sinoatrial node

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