The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of δ₂-opioid receptor stimulation

Abstract

. The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of ␦ 2-opioid receptor stimulation. Am J Physiol Heart Circ Physiol 291: H2318 -H2326, 2006. First published June 30, 2006 doi:10.1152/ajpheart.00455.2006.-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 THE SINOATRIAL (SA) node or cardiac pacemaker is densely innervated by sympathetic and parasympathetic nerve fibers that moderate automaticity through the local nodal release of norepinephrine and acetylcholine. In addition to direct innervation, multiple factors within the node modify both spontaneous activity and neurotransmitter release. Among these moderators, cardiac opioids appear to be potentially important neuromodulators (3, 9, 10).Proenkephalin mRNA is more abundant in the heart than most other tissues, including the brain (12). Enkephalins are found in the heart, and despite the stoichiometric advantage afforded met-enkephalin (ME), ME-arginine-phenylalanine (MEAP) concentrations are higher in the heart than any of the other three enkephalins (2, 19, 29). ME, leucine-enkephalin (LE), and MEAP have all been demonstrated to alter vagally induced bradycardia when introduced into the SA node by microdialysis (9 -11, 13). The op...

Sphingolipids in Obesity, Type 2 Diabetes, and Metabolic Disease

“…Furthermore, the contributions of particular enzymes of sphingolipid metabolism and individual N -acyl chain lengths have been utterly neglected. Additionally, it should be noted that, while much of the literature on sphingolipids in the diabetic heart focuses on their roles in diabetic cardiomyopathy, they also play important roles in injury following ischemia and reperfusion (I/R) (Maulik et al 1993; Bielawska et al 1997; Theilmeier et al 2006) and in defects in electrical conductance (Constable et al 2003) and autonomic nervous function (Tessari et al 1988; Davis et al 2006), all of which are major concerns in the diabetic heart. Finally, the role of sphingolipids in diabetic glucotoxicity in the heart has been abjectly neglected, despite its potential importance.…”

δ-Opioid receptors: Pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity

“…Opioids are notorious for their ability to downregulate receptors following repeated exposure. Prior studies also indicate that repeated sublethal ischemic stress or exposure to GM-1 both result in a decline in the vagolytic δ 2 -OR response [Deo et al, 2009; Davis et al, 2006]. In addition to the hypoxic stress, IHT appears to produce both an increase in GM-1 and a decline in δ-OR content.…”

“…This would however be completely congruent with the current functional and molecular observations if the decline in receptor labeling were primarily from the larger pool of δ 2 -ORs. In support of this concept, administering GM-1 into the SA node by dialysis produced a progressive elimination of the vagolytic δ 2 -OR response [Davis et al, 2006] presumably by enhancing the lipid raft environment in which the prejunctional δ-OR operates. This part of the subtype hypothesis will require pharmacologic confirmation with subtype selective antagonists [Farias et al, 2003].…”

“…This improved vagal function appears to result from a shift in the local receptor environment that favors the vagotonic δ 1 -OR [Farias et al, 2001] at the expense of vagolytic δ 2 -ORs. The environmental shift may result from local changes in the vagotonic neurotropin monosialoganglioside-1 (GM-1) [Davis et al, 2006]. …”

Endogenous opiates and behavior: 2009

“…Activation of DOR through the opening of KATP channels reduces the severity of post resuscitation myocardial dysfunction (332). The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of delta2-opioid receptor stimulation (265). Repeated delta-1 opioid receptor stimulation reduces delta2-opioid receptor responses in the sinoarterial node (275).…”