δ-2 Opioid Receptor Plasticity and GM-1
δ-2 Opioid receptor plasticity and GM-1. Shavsha Davis, Masters of Science (Biomedical Sciences), May 2005, 56 pp, 3 tables, 10 figures.
δ-2 Opioid receptor plasticity and GM-1. Shavsha Davis, Masters of Science (Biomedical Sciences), May 2005, 56 pp, 3 tables, 10 figures. The native cardiac enkephalin, methionine-enkephalin-arginine-phenylalanine (MEAP) altered vagally induced bradycardia when introduced in the sinoatrial (SA) node by microdialysis. The responses to MEAP were bimodal in character with lower doses enhancing bradycardia while higher doses suppressed bradycardia. The opposing vagotonic and vagolytic effects were mediated respectively by δ-1 and δ-2 subtypes of the same δ-opioid receptor. The opposing responses were blocked by sub-type specific antagonists. When the mixed agonist, MEAP was evaluated after treatment with the monosialosyl ganglioside, GM-1, the δ-1-mediated vagotonic response was enhanced and the δ-2 mediated vagolytic response was reduced. Subsequent studies were conducted to test the hypothesis that increased GM-1 content in the SA node reduced the δ-2 vagolytic response independent of a coincident increase in competing δ-1-meiated vagotonic activity. The selective δ-2-agonist, deltorphin was introduced into the SA node by microdialysis to evaluate initial δ-2-vagolytic responses. The right vagus nerve was stimulated and the expected decline in heart rate was significantly attenuated by deltorphin. GM-1 was then perfused into the nodal interstitium for one hour without a significant change in vagal transmission. Following GM-1, deltorphin was reintroduced and a clear attenuation of the deltorphin’s vagolytic response was observed. Similar results were obtained intime controls when GM-1 was omitted. In both cases the δ-1 selective antagonist 7-benzylidenaltrexone (BNTX) failed to restore the vagolytic response was added afterward. However when added to the time controls early in the protocol, BNTX completing prevented the loss in the vagolytic response. When both the initial deltorphin and GM-1 were omitted the vagolytic response was significantly improved. In summary, the initial study with the mixed agonist, MEAP suggested that GM-1 reduced the δ-2-vagolytic response. This was confirmed when the relatively selective δ-2-agonist, deltorphin, was substituted for MEAP. Subsequent protocols suggested that deltorphin and GM-1 produced qualitatively similar losses in the vagolytic response that were not restored by subsequent δ-1-receptor blockade. Thus, the attenuation of the δ-2 response was not due to the addition of competing δ-1 mediated vagotonic activity. The elimination of the deltorphin mediated attrition of the δ-2 response by BNTX indicated that the declining response was mediated by δ-1 receptors. Thus GM-1, deltorphin, and time all interact to modify subsequent δ-2-mediated vagolytic responses. The specific contribution of deltorphin in this process was mediated by the activation of δ-1-receptors. Whether deltorphin has intrinsic δ-1 activity or causes the release of an endogenous δ-1 agonist is unclear. The specific mechanism by which the δ-1 and δ-2 opioid receptors interact likewise remains to be determined.