Browsing by Subject "Systems Neuroscience"
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Item Effects of Endurance Training on Aortic and Carotid Baroreflex Function(1999-06-01) Smith, Scott Alan; Peter B. Raven; Michael Smith; Patricia A. GwirtzSmith, Scott Alan, Effects of Endurance Training on Aortic and Carotid Baroreflex Function. Doctor of Philosophy (Biomedical Sciences), June 1999; 122 pp; 8 tables; 10 figures; bibliography, 148 titles. Arterial bareflex control of cardiac function is dependent upon afferent input from both the aortic arch and carotid sinus bareceptors. Extensive research in animals has generated conflicting results as to the range of arterial pressures over which each baroreflex operates. Further, the complex integration of afferent signals within the medullary cardiovascular center, in reference to aortic and carotid baroreceptor input, has been characterized as additive, inhibitory, and facilitatory in nature. Such reports make it difficult to draw definitive conclusions about the behavior or central neural processing within the brainstem. In addition, these relationships have yet to be examined in humans. Therefore, the purpose of the investigations described herein, was to quantify the range of pressures over which the arterial aortic and carotid baroreflexes operate as well as to describe the interactive relationship between the aortic and carotid baroreceptors. In order to investigate these questions, we isolated the arterial, aortic, and carotid-cardiac baroreflexes in volunteer subjects generating sigmoidal stimulus-response curves for each reflex arc. Arterial and aortic baroreflex (ABR) control of heart rate (HR) was assessed by inducing graded increases and decreases in mean arterial pressure (MAP) by bolus infusion of the vasoactive agents phenylephrine (PE) and sodium nitroprusside (SN), respectively. Carotid baroreflex (CBR) function was determined utilizing ramped five second pulses of both pressure and suction applied to the carotid sinus via a neck chamber collar, independent of drug administration. The MAP at which the threshold and saturation were elicited did not differ among the reflexes examined indicating each reflex operated over a similar range of arterial pressures. Further, the simple sum of the independently driven HR response ranges of the CBR and ABR was significantly greater than that produced when both baroreceptor populations were concomitantly stimulated (i.e. arterial baroreflex) suggesting an inhibitory interaction. To investigate differential baroreflex control of HR in response to chronic endurance exercise training, a second investigation was designed implementing the reflex isolation techniques described previously. Stimulus-response relationships were compared between high fit (maximal oxygen uptake, VO2max [greater than] 60ml˖kg-1˖min-1) and average fit (VO2maxml˖kg-1˖min-1) individuals. Interestingly, neither the range of operating pressures for each reflex nor the integrative relationship between the ABR and CBR were altered as a result of aerobic training. However, the HR response range elicited from the aortic baroreceptors as a result of hypotensive and hypertensive insult was markedly attenuated in the aerobically trained population compared to their sedentary counterparts, exclusively causing a requisite reduction in arterial baroreflex sensitivity.Item Endothelin-1-Induced Signaling Involved in Extracellular Matrix Remodeling(2006-12-01) He, Shaoqing; Thomas Yorio; Neeraj Agarwal; Peter KoulenET-1-Induced Signaling in ECM Remodeling in Astrocytes. Shaoqing He, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107. ET-1 levels are elevated under pathophysiological conditions, including glaucoma, however, ET-1’s ocular functions are not fully documented. Therefore, ET-1-induced signaling and ECM remodeling in astrocytes and at the optic nerve head were determined in this study. Three signaling pathways, including ERK1/2, PKC, and P13 kinase, were involved in ET-1-medicated cell proliferation of U373MG astrocytoma cells. Blocking one of these pathways completely abolished cell proliferation. It appeared that ERK1/2 activation was involved, but was independent of PKC and P13 kinase activation by ET-1. It was also determined that the ETB receptor was the dominant receptor involved in ERK1/2 phosphorylation and cell proliferation. In addition, ERK1/2 phosphorylation was not transactivated by the EGF receptor by ET-1. The studies also indicated that there was no activation of c/nPKC, although PKC was involved in cell proliferation. In U373MG astrocytoma cells, MAPK-ERK, PKC and P13K pathways appear to exert their roles in parallel without a direct, apparent “cross-talk”. Based on the signaling pathways obtained from U373MG astrocytoma cells, the regulation of MMPs/TIMPs and fibronectin in ET-1-activated human optic nerve head astroctyes (hONAs) was also determined. ET-1 not only induced rapid phosphorylation of ERK1/2 and PKC βI/ βII/δ but also increased the activity of MMP-2 and the expression of TIMP=1 and 2. The activity of MMP-2 was enhanced in the presence of inhibitors of MAPK or PKC in hONAs, whereas the expression of TIMP-1 and 2 was abolished. ET-1 increased the soluble fibronectin (FN) expression as well as FN matrix formation, however, the expression and deposition of FN were MAPK- and PKC-independent, whereas expression and activity of MMps and TIMPs were MAPK- and PKC-dependent. Therefore, ET-1 shifted the balance of MMPs/TIMPs and substrates that altered the ECM composition and subsequently let to ECM remodeling in activated hONA cells. ET-1’s effects on ECM remodeling at the optic nerve head were also examined following intravitreal administration of ET-1 in rats. The increased expression of MMP-9 and collagen VI was detected in both ETB deficient rats and wildtype Wistar rats post ET-1 intravitreal injection for 2 and 14 days, whereas the deposition of FN and collagen IV was unchanged. There was no significant difference in staining of MMP-9 and collagen VI between ETB deficient rats and wildtype Wistar rats. In this study, ECM remodeling was demonstrated in rats injected with ET-1 into the vitreous. Such changes in the ECM seen in the current study provide additional insight into the mechanisms that might explain the glaucomatous changes observed in ET-1-injection or perfusion models. In summary, ET-1 not only activated several signaling pathways in cell proliferation of astrocytes, but also modulated the expression of ECM molecules in vitro and in vivo, indicating that ET-1 plays a regulatory role in ECM remodeling. These effects coupled with observations that ET-1 levels are elevated in glaucoma patients, suggests that ET-1 may be involved in glaucomatous optic neuropathy.Item Influence of Thermoregulatory and Nonthermoregulatory Control Mechanisms of Arterial Blood Pressure During Recivert from Exercise in Humans(2001-05-10) Carter, Robert; Michael L. Smith; Robert L. Kaman; Thomas YorioCarter, III Robert, Thermoregulatory and nonthermoregulatory control of arterial pressure during recovery from exercise in humans. Doctor of Philosophy (Biomedical Sciences). May 2001; 153p; 4 tables, 17 figures; 100 titles. The mechanisms of arterial blood pressure control during exercise is well established; however, much less is known about the regulation of arterial blood pressure immediately after intense or prolonged dynamic exercise. Inactive recovery from dynamic exercise is associated with cessation of the primary exercise stimuli from the brain (central command), Skeletal muscle pumping, which contributes to increases in venous return during exercise is also stopped during inactive recovery from exercise. Thus, the skeletal muscle pump and central command each contribute importantly to elevation and maintenance of arterial blood pressure regulation and cerebral blood flow during exercise. When exercise is intense and/or prolonged, the resulting thermal load exacerbates the challenge to maintain arterial blood pressure and cerebral blood flow both during exercise and particularly during recovery from exercise and thereby increases the risk of syncope. Recently, we found that the skeletal muscle pump plays a major role in arterial blood pressure control during recovery from brief (3 min), mild (60% of maximal HR) exercise in which there was no thermal load. However, how the mechanisms of arterial pressure regulation operate during recovery from intense or prolonged exercise when a thermal load occurs is unknown. Therefore, the purpose of the investigations described herein, was to quantify the mechanisms of the carotid baroreflex function, central command, and the skeletal muscle pump when a thermal stress occurs on arterial blood pressure regulation during recovery from exercise in humans. In addition, differences in arterial blood pressure regulation in women and men during recovery from exercise were addressed in women and men. To investigate these mechanisms, we investigated the carotid-cardiac baroreflex function, cardiovascular, and thermoregulatory responses in volunteer subjects during inactive and active recovery from prolonged exercise improved the function of the baroreflex by increasing the functional reserve of the reflex to buffer against hypotensive stimuli. Our data also suggest that thermoregulatory factors contribute to decreases in MAP after inactive recovery from exercise. In addition, the metabolic state of skeletal muscle during longer duration exercise (15 min) may contribute to these responses during inactive recovery from exercise. These results support the hypothesis that thermal stress contributes to the rapid decreases in arterial blood pressure during inactive recovery following dynamic exercise. To investigate gender differences in arterial pressure regulation during recovery from exercise, we compared 11 women and 8 men during 3 min of exercise and 5 min of inactive and active recovery from exercise. Interestingly, at 1 minute after exercise, MAP decreased less during inactive recovery in men when compared to women. This difference was due to greater decreases in SV and less increase in TPR during inactive recovery from exercise in women compared to men. MAP decreased less during active recovery in men when compared to women. These findings suggest that women may have increased risk of post-exercise orthostatic hypotension and that active recovery from exercise may reduce this risk.Item Leucine-Enkephalin and Sympathetic Control of Heart Rate(2001-12-01) Stanfill, Amber; Caffrey, James L.; Downey, H. Fred; Shi, XiangrongStanfill, Amber A., Leucine-enkephalin and Sympathetic Control of Heart Rate. Master of Science (Biomedical Sciences), December, 2001, 51 pp., 1 table, 4 figures, references, 48 titles. The following study examined the role of leucine-enkephalin in the sympathetic regulation of the cardiac pacemaker. Leucine-enkephalin (0.3 mM) was administered, by microdialysis into the interstitium of the sinoatrial node in 10 mongrel dogs in conjunction with either sympathetic nerve stimulation or infused norepinephrine. In study one, the right cardiac sympathetic nerves were isolated as they exit the stellate ganglion and stimulated to produce graded (low, 20-30; high 40-50 bpm) increases in heart rate. Once stimulation frequencies were determined, leucine-enkephalin (0.3mM) was added to the dialysis inflow and perfused at 5: 1/min thereafter. The sympathetic stimulations were repeated after 5 and 20 min exposure to leucine-enkephalin. The resulting increases in heart rate during sympathetic stimulation were attenuated at both low (18.2 ±1.3 to 11.4 ±1.4 bpm) and high (45 ±1.5 to 22.8 ±1.5 bpm) frequency stimulation. The degree of inhibition was nearly identical after 20 minutes exposure providing no evidence for a progressively evolving response and for desensitization. Vagal function was also evaluated at 5 and 20 min by stimulating the right cervical vagus at 1 and 3 Hz. Leucine-enkephalin reduced the vagal bradycardia approximately 50% at both time intervals. The administration of the delta-selective opioid antagonist, naltrindole, restored only one third of the sympathetically medicated tachycardia. The same dose of naltrindole completely reversed the coincident vagolytic of leucine-enkephalin. These observations suggested that the sympatholytic effect was either non-opioid or mediated by a different opioid receptor subtype. Study two was conducted to determine if the sympatholytic effect was prejunctional and post-junctional in character. Norepinephrine was added to the dialysis inflow into the SA node in a concentration (6-9 μM) sufficient to produce an intermediate increase in heart rate. The average increase in heart rate was 35.2 ±1.8 bpm. Leucine-enkephalin was then combined with norepinephrine and sympathetic and parasympathetic responses were recorded at 5-min intervals for 20 minutes. The tachycardia mediated by added norepinephrine was unaltered by leucine-enkephalin or the subsequent addition of naltrindole. At the same time intervals, vagal control of heart rate was reduced by more than 50% and then completely restored by naltrindole. When combined with observations in study one, the data support the conclusion that the local nodal sympatholytic effect of leucine-enkephalin was the result of a reduction in the effective interstitial concentration of norepinephrine and not the result of a post-junctional interaction between leucine-enkephalin and norepinephrine.Item Mechanisms of Chemoreflex Control of Muscle Sympathetic Nerve Activity and Blood Pressure in Humans(2004-05-01) Hardisty, Janelle M.; Smith, Michael; Shi, Xiangrong; Clark, MichaelHardisty, Janelle M., Mechanisms of Chemoreflex Control of Muscle Sympathetic Nerve Activity and Blood Pressure in Humans. Doctor of Philosophy (Integrative Physiology), May 2004. The mechanisms linking obstructive sleep apnea (OSA) and cardiovascular disease are not fully understood; however, studies report patients with OSA exhibit chronic elevations in muscle sympathetic nerve activity (MSNA). This appears to be due to altered chemoreflex control of MSNA, mediated primarily by hypoxia. Yet, a correlation between degree of hypoxia and chemoreflex control of MSNA is unknown. Therefore, it was evaluated whether degree of hypoxia occurring during apnea determines the sympathoexcitatory and blood pressure responses, and whether these responses are augmented in OSA patients. Additionally, it was studied whether altered chemoreflex function in OSA patients is predictive of blood pressure response to apnea. In a clinical setting, the blood pressure response to voluntary apnea was determined to evaluate whether this could be used as a non-invasive measure of chemoreflex gain in OSA. Finally, the effect of hyperoxia on MSNA was studied to determine whether 15 min of hyperoxia, following intermittent hypoxic apnea, reverses the elevation of MSNA and altered chemoreflex control of MSNA. Consistent with the hypotheses, a relationship between MSNA responses, blood pressure response and level of hypoxia were determined. MSNA and peak systolic pressure responses were augmented in OSA subjects (p≤0.05 and p≤0.05, respectively), as well as, chemoreflex gain (p≤0.05). Clinically, peak systolic pressure responses to apnea were augmented in OSA patients (p˂0.001). Finally, basal MSNA and chemoreflex control of MSNA, following hyperoxia, was not different from baseline through 180 min of recovery (p=0.940 and p=0.278, respectively). These data support the hypotheses that chemoreflex gain is predicative of the blood pressure response; and furthermore, the MSNA and blood pressure responses to hypoxic apnea are augmented in OSA. Additionally, peak systolic pressure responses to voluntary apnea are augmented in OSA. Additionally, peak systolic pressure responses to voluntary apnea are augmented in OSA patients and could possibly be used as a marker of chemoreflex gain. Moreover, these data support the hypothesis that hyperoxia can reverse basal sympathoexcitation and augmented chemoreflex control of MSNA, associated with hypoxic apnea, supporting that elevations in MSNA are hypoxia mediated.Item Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed(2000-08-01) Pearlman, Eric Brian; Barbara Barron; Patricia A. Gwirtz; Michael L. SmithPearlman, Eric B., Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed. Master of Science (Biomedical Science), August, 2000, 37 pp., 3 tables, 11 figures, references, 20 titles. Methionine enkephalin arginine phenylalanine (MERF) has been shown to be co-stored with catecholamines in vesicles. The catecholamines appear to decrease the degradation rate of 3H-MERF in vitro. The aim of this study is to investigate the spillover and metabolism of MERF across the canine heart vascular bed. I hypothesize that 3H-MERF is either degraded in the plasma or taken up and degraded by the heart. I further hypothesize that the exogenous catecholamine, isoproterenol, inhibits or reduces the rate of MERF degradation. Mongrel dogs were anesthetized and instrumented to record cardiovascular parameters, infuse 3H-MERF, and obtain blood samples across the heart. Blood samples were taken before and after stopping 3H-MERF infusion to evaluate kinetics, show steady state, and test the effect of treatments. Steady state concentration of 3H-MERF was observed after 30 min of infusion. Chromatography separated intact from degraded 3H-MERF. Three experimental groups were used: control, propranolol plus isoproterenol, and propranolol only. Blockade of β-receptors was necessary to prevent changes in coronary blood flow. Propranolol bolus (0.2 mg/kg) was administered IV at 50 min. 3 μg/min isoproterenol or 0.5 ml/min normal saline was infused starting at 70 min until the end of sample collection. The 3H-MERF venous-arterial (V-A) difference prior to treatment was negative, indicating degradation in the plasma or uptake and degradation by the heart. The 75 min V-A difference was used to calculate the effect of the infusions on the degradation or uptake of the 3H-MERF; this value was unchanged by any treatment. Spillover of 3H-MERF was significantly lower in the propranolol + isoproterenol dogs (p [less than] 0.05) compared to propranolol only treatment at 75 min. Heart rate was significantly lower for the propranolol only group compared to control. Blood pressure and change in coronary flow were unchanged. In conclusion, isoproterenol does not affect the metabolism of 3H-MERF across the canine heart vascular bed. Propranolol, however, does increase the intact 3H-MERF in the plasma, but additional β adrenergic blockade agents need to be investigated to determine the mechanism by which this takes place.Item Sexually Dimorphic Anxiety-Like Interoceptive Discriminative Stimuli(1997-12-01) Jung, Marianna E.; Walls, Cleatus; Downey, H. Fred; Forster, MichaelJung, Marianna E., Sexually Dimorphic Anxiety-Like Interoceptive Discriminative Stimuli. Doctor of Philosophy (Biomedical Sciences), December 1997, 150 pp, introduction, 2 chapters, discussion, bibliography, 109 titles. This study compared gender differences in the anxiogenic stimuli induced by either a GABA-A antagonist, pentylenetetrazol (PTZ) or by a 5-HT1b/2 agonist, m-chlorophenylpiperazine (m-CPP) before and during ethanol withdrawal (EW). Rats were trained to discriminate either PTZ (16mg/kg, IP) or m-CPP (1.2 mg/kg, IP) from saline in a two lever choice task for food reward. Male and female rats were gonadectomized or sham-operated, and ovariectomized (OVX) female rats were tested during replacement treatment with 17β estradiol (2.5 mg, 21 day release, sc). The dose-response for the discrimination of the interoceptive stimulus (IDS) produced by PTZ (0-16 mg/kg) or m-CPP (0 to 1.2 mg/kg) was measured under all hormonal conditions. For m-CPP trained rats, latency to first lever-press response was also tested. Results: sham and estradiol-replaced female rats had higher ED50s for discrimination of the PTZ or m-CPP IDS than intact males or OVX rats. There is a dose-related impairment of operant responding after mCPP injection. Sham and estradiol replaced OVX rats showed an increased delay to the initiation of response after m-CPP injection as compared to sham or castrated male rats or OVX rats that showed no effect at the doses tested. Rats then received a chronic ethanol diet (6.5%) for 10 days. At twelve hours of ethanol withdrawl, they were tested for lever selection after saline injection. Fewer sham female and estradiol-replaced female rats responded on the drug lever during acute EW as compared to sham male, castrated or OVX rats. In general, the anxiogenic drug lever selection of OVX rats resembled that of male rats but was restored toward that of sham female rats by estradiol replacement. Castration did not alter the response of male rats to either PTZ or mCPP. Serum β –estradiol concentrations were determined by radioimmunoassay for sham, OVX, and estradiol-replaced female rats. The concentration was significantly higher in hormone-replaced female rats than in OVX. The estradiol concentration in sham female rats showed a cyclic pattern over 4 consecutive days, but this pattern did not correlate with any difference in IDS. Blood ethanol concentration (BEC) was determined using head space gas chromatography. BEC was higher in intact female rats than in intact male rats after ethanol injection (2 g/kg, ip), but did not differ during EW. Conclusions: females produce less anxiogenic IDS in response to either GABA inhibition or 5-HT1b/2 activation, but are more impaired by m-CPP in their ability to initiate operant responses than male rats. In addition, fewer intact females developed a spontaneous IDS during EW than males which is not the result of lower BEC. Estrogen appears to play a trophic role in altering responsiveness to anxiogenic stimuli.Item The Role of Advanced Glycation End Products in Brain Aging(2007-10-01) Thangthaeng, Nopporn; Michael J. Forster; Tina MachuThangthaeng, Nopporn, The Role of Advanced Glycation End Products in Brain Aging. Doctor of Philosophy (Biomedical Sciences), October, 2007, 178 pp., 9 tables, 6 figures, bibliography, 213 titles. Glycoxidation is a process of post-translational modification of proteins, involving both glycation and oxidation that ultimately generated advanced glycation end products (AGEs). Glycoxidation, which pay promote oxidative stress and disrupt protein structure and function, is hypothesized to be responsible for pathological conditions related to aging, diabetes, neurodegenerative diseases, and degenerative ophthalmic diseases. Previous studies have demonstrated that AGEs accumulate in the brains of aged animals and humans, yet few studies have directly addressed the possibility that AGEs are a cause of age-related brain dysfunction. Therefore, the overall purpose of the present studies was to examine the role AGEs in normal brain again and the associated decline in cognitive and psychomotor function. In order to achieve the goals, two different approaches were taken. The first approach involved (i) determining whether or not AGEs accumulated in different regions of the brain as a function of age and (ii) determining whether these changes were correlated with individual differences in the ability of old mice to perform in tests of cognitive and psychomotor function. Age-associated accumulation of CML, a predominant form of AGEs in vivo, and expression of receptor for AGEs (RAGE) protein, inferred from densitometry quantification of immunoblots in different regions of the brain, were assessed by comparing groups of 8-or 25-month old mice. The 25-month-old mice were administered a series of behavioral tests to assess cognitive and psychomotor function prior to assessment of glycation status. In the second approach, groups of mature (6 mos) and older mice (18 mos) were fed with a control diet or a diet enriched with galactose (49% of caloric content), an intervention that was expected to promote formation of AGEs. The mice were subsequently tested for impairment of their cognitive and psychomotor functions after 8 weeks on the assigned diet. Upon completion of the behavioral tests (after 14 weeks on diet), amounts of CML and RAGE protein were assessed through densitometric analyses of the immunoblots. The main findings from the first approach were that (i) there was a robust increase in CML content and expression of RAGE protein in the aged mouse brain that occurred in a region-specific manner; (ii) the relative amounts of CML and RAGE were not closely associated with the degree of age-related impairment of mice tested for brain function. The main findings from the second approach were that high dietary galactose: (i) failed to induce aged-like behavioral impairments in young/mature mice; (ii) exacerbated age-related impairment of some psychomotor functions and (iii) had no significant effects on glycation status or oxidative damage. Comparison of the experimental outcomes from the first and second approaches was complicated by a difference in the fat content of the diets fed to the mice in the two studies, which had an apparent effect on the amounts of AGEs and protein oxidation present in young mice. However, considering the results of the two studies independently warrants the following conclusions: (i) Amounts of AGEs do not predict individualized brain aging as assessed by neurobehavioral impairment and may instead by largely reflective of chronological age. (ii) Diets enriched with galactose may produce deleterious effects in older mice that do not involve a change in oxidative damage or glycation status. Overall, these studies provide little support for a specific role of glycoxidation in normal brain aging. It is impossible that the extent of accrual of AGEs in the normally aging brain is insufficient to affect cellular function, whereas larger accumulations of AGEs may be associated with various pathological conditions discussed in the literature.Item δ-2 Opioid receptor plasticity and GM-1(2005-05-01) Davis, Shavsa; Caffrey, James; Mallet, Robert T.; Singh, Meharvanδ-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.