Date of Award

5-1-2005

Degree Type

Restricted Access Thesis

Degree Name

Master of Science

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

James Caffrey

Second Advisor

Robert Mallet

Third Advisor

Meharvan Singh

Abstract

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 into 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 independent of a coincident increase in competing the δ-1-mediated 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 in time controls when GM-1 was omitted. In both cases the δ-1 selective antagonist 7-benzylidenaltrexone (BNTX) failed to restore the vagolytic response when added afterward. However when added to the time controls early in the protocol, BNTX completely prevented the loss in the vagolytic response. When both the intial 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 completing δ-1-mediated vagotonic activity. The elimination of the deltorphin mediated attrition of the δ-2 response by the 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.

Comments

δ-2 Opioid receptor plasticity and GM-1. Shavsha Davis, Masters of Science (Biomedical Sciences), May 2005, 56 pp, 3 tables, 10 figures. W 4.5 D264D 2005

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