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The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of ₂-opioid receptor stimulation

Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas

Submitted 4 May 2006 ; accepted in final form 26 June 2006

The cardiac enkephalin, methionine-enkephalin-arginine-phenylalanine (MEAP), alters vagally induced bradycardia when introduced by microdialysis into the sinoatrial (SA) node. The responses to MEAP are bimodal; lower doses enhance bradycardia and higher doses suppress bradycardia. The opposing vagotonic and vagolytic effects are mediated, respectively, by ₁ and ₂ phenotypes of the same receptor. Stimulation of the ₁ receptor reduced the subsequent ₂ responses. Experiments were conducted to test the hypothesis that the -receptor interactions were mediated by the monosialosyl ganglioside GM-1. When the mixed agonist MEAP was evaluated after nodal GM-1 treatment, ₁-mediated vagotonic responses were enhanced, and ₂-mediated vagolytic responses were reduced. Prior treatment with the ₁-selective antagonist 7-benzylidenaltrexone (BNTX) failed to prevent attrition of the ₂-vagolytic response or restore it when added afterward. Thus the GM-1-mediated attrition was not mediated by ₁ receptors or increased competition from ₁-mediated vagotonic responses. When GM-1 was omitted, deltorphin produced a similar but less robust loss in the vagolytic response. In contrast, however, to GM-1, the deltorphin-mediated attrition was prevented by pretreatment with BNTX, indicating that the decline in response after deltorphin alone was mediated by ₁ receptors and that GM-1 effectively bypassed the receptor. Whether deltorphin has intrinsic ₁ activity or causes the release of an endogenous ₁-agonist is unclear. When both GM-1 and deltorphin were omitted, the subsequent vagolytic response was more intense. Thus GM-1, deltorphin, and time all interact to modify subsequent ₂-mediated vagolytic responses. The data support the hypothesis that ₁-receptor stimulation may reduce ₂-vagolytic responses by stimulating the GM-1 synthesis.

bradycardia; deltorphin; heart rate

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