The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of [delta]^sub 2^-opioid receptor stimulation

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 δ^sub 1^ and δ^sub 2^ phenotypes of the same receptor. Stimulation of the δ^sub 1^ receptor reduced the subsequent δ^sub 2^ responses. Experiments were conducted to test the hypothesis that the δ-receptor interactions were mediated by the monosialosyl ganglioside GM-1. When the mixed agonist MEAP was evaluated after nodal GM-1 treatment, δ^sub 1^-mediated vagotonic responses were enhanced, and δ^sub 2^-mediated vagolytic responses were reduced. Prior treatment with the δ^sub 1^-selective antagonist 7-benzylidenaltrexone (BNTX) failed to prevent attrition of the δ^sub 2^-vagolytic response or restore it when added afterward. Thus the GM-1-mediated attrition was not mediated by δ^sub 1^ receptors or increased competition from δ^sub 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 δ^sub 1^ receptors and that GM-1 effectively bypassed the receptor. Whether deltorphin has intrinsic δ^sub 1^ activity or causes the release of an endogenous δ^sub 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 δ^sub 2^-mediated vagolytic responses. The data support the hypothesis that δ^sub 1^-receptor stimulation may reduce δ^sub 2^-vagolytic responses by stimulating the GM-1 synthesis. [PUBLICATION ABSTRACT]