naltrindole and Bradycardia

MCRT (YPFPFRTic-NH(2)) is a chimeric opioid peptide based on morphiceptin and PFRTic-NH(2). In order to assess the cardiovascular effect of MCRT, it was administered by intravenous (i.v.) injection targeting at the peripheral nervous system and by intracerebroventricular (i.c.v.) injection targeting at the central nervous system. Naloxone and L-NAME were injected before MCRT to investigate possible interactions with MCRT. Results show that administration of MCRT by i.v. or i.c.v. injection could induce bradycardia and decrease in mean arterial pressure (MAP) at a greater degree than that with morphiceptin and PFRTic-NH(2). When MCRT and NPFF were coinjected, we observed a dose-dependent weakening of these cardiovascular effects by MCRT. Because naloxone completely abolished the cardiovascular effects of MCRT, we conclude that opioid receptors are involved in regulating the MAP of MCRT regardless of modes of injection. The effect of MCRT on heart rate is completely dependent on opioid receptors when MCRT was administered by i.c.v. instead of i.v. The central nitric oxide (NO) pathway is involved in regulating blood pressure by MCRT under both modes of injection, but the peripheral NO pathway had no effect on lowering blood pressure mediated by MCRT when it was administered by i.c.v. Based on the results from different modes of injection, the regulation of heart rate by MCRT mainly involves in the central NO pathway. Lastly, we observed that the cardiovascular effects of MCRT such as bradycardia and decrease of blood pressure, were stronger than that of its parent peptides. Opioid receptors and the NO pathway are involved in the cardiovascular regulation by MCRT, and their degree of involvement differs between intravenous and intracerebroventricular injection.

Topics: Analgesics, Opioid; Animals; Blood Pressure; Bradycardia; Endorphins; Heart Rate; Hypotension; Injections, Intravenous; Injections, Intraventricular; Male; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Rats; Rats, Wistar

This study examined the role of leucine-enkephalin (LE) in the sympathetic regulation of the cardiac pacemaker. LE was administered by microdialysis into the interstitium of the canine sinoatrial node during either sympathetic nerve stimulation or norepinephrine infusion. In study one, the right cardiac sympathetic nerves were isolated as they exit the stellate ganglion and were stimulated to produce graded (low, 20-30 bpm; high 40-50 bpm) increases in heart rate (HR). LE (1.5 nmoles/min) was added to the dialysis inflow and the sympathetic stimulations were repeated after 5 and 20 min of LE infusion. After 5 min, LE reduced the tachycardia during sympathetic stimulation at both low (18.2 +/- 1.3 bpm to 11.4 +/- 1.4 bpm) and high (45 +/- 1.5 bpm to 22.8 +/- 1.5 bpm) frequency stimulations. The inhibition was maintained during 20 min of continuous LE exposure with no evidence of opioid desensitization. The delta-opioid antagonist, naltrindole (1.1 nmoles/min), restored only 30% of the sympathetic tachycardia. Nodal delta-receptors are vagolytic and vagal stimulations were included in the protocol as positive controls. LE reduced vagal bradycardia by 50% and naltrindole completely restored the vagal bradycardia. In Study 2, additional opioid antagonists were used to determine if alternative opioid receptors might be implicated in the sympatholytic response. Increasing doses of the kappa-antagonist, norbinaltorphimine (norBNI), were combined with LE during sympathetic stimulation. NorBNI completely restored the sympathetic tachycardia with an ED50 of 0.01 nmoles/min. A single dose of the micro -antagonist, CTAP (1.0 nmoles/min), failed to alter the sympatholytic effect of LE. Study 3 was conducted to determine if the sympatholytic effect was prejunctional or postjunctional in character. Norepinephrine was added to the dialysis inflow at a rate (30-45 pmoles/min) sufficient to produce intermediate increases (35.2 +/- 1.8 bpm) in HR. LE was then combined with norepinephrine and responses were recorded at 5-min intervals for 20 min. The tachycardia mediated by added norepinephrine was unaltered by LE or LE plus naltrindole. At the same 5-min intervals, LE reduced vagal bradycardia by more than 50%. This vagolytic effect was again completely reversed by naltrindole. Collectively, these observations support the hypothesis that the local nodal sympatholytic effect of LE was mediated by kappa-opioid receptors that reduced the effective interstitial concentration of

Topics: Adrenergic alpha-Agonists; Animals; Blood Pressure; Bradycardia; Dogs; Enkephalin, Leucine; Female; Heart Rate; Male; Microdialysis; Naltrexone; Narcotic Antagonists; Norepinephrine; Receptors, Opioid; Sinoatrial Node; Sympathetic Nervous System; Tachycardia; Vagus Nerve

Endogenous opioids modulate attention-related heart rate responses evoked by novel stimuli and conditioned signals in ways that differ from their better-known effects on motivation and memory functions. We investigated the role of delta-opioids in modulating bradycardiac orienting and Pavlovian conditioned responses in rabbits, following i.v. treatment with the highly selective delta-receptor antagonist naltrindole (NTI; 0.037-0.370 mg/kg). When administered immediately before testing, NTI induced modest but detectable effects: the lowest dose increased cardiac discrimination near the end of the first training session, whereas the higher doses of NTI impaired discrimination, compared to saline-treated controls. NTI treatment immediately before testing also appeared to promote habituation of bradycardiac orienting responses elicited by novel tones, but NTI did not alter unconditioned heart rate responses following tone-shock pairs or extinction of conditioned responses. In contrast, the low dose of NTI administered 20 min, rather than immediately before testing, facilitated conditioned bradycardia during extinction, as well as during training. These results provide evidence that endogenous delta-opioid modulators normally delay the disappearance of bradycardiac orienting responses during habituation, inhibit or promote the development of bradycardiac conditioned responses during Pavlovian training depending on dose, and promote the disappearance of conditioned responses during extinction. These findings suggest that endogenous delta-opioid activity, probably involving both peripheral and central systems, coincides with, and may reflect, uncertainty about stimulus significance.

Topics: Animals; Attention; Bradycardia; Conditioning, Psychological; Female; Habituation, Psychophysiologic; Heart Rate; Male; Naltrexone; Narcotic Antagonists; Narcotics; Rabbits