Opiate receptors and the endorphin-mediated cardiovascular effects of clonidine in rats: evidence for hypertension-induced mu-subtype to delta-subtype changes.

Abstract

Effects of opiate receptor antagonists on centrally mediated cardiovascular responses to clonidine and j8-endorphin were studied in urethane-anesthetized spontaneously hypertensive Okamoto-Aoki rats (SHR), normotensive Sprague-Dawley rats, and Sprague-Dawley rats made hypertensive with deoyycorticosterone pivalate/salt. Microinjection of 270 pmol of naloxone into the nucleus tractus solitarli (NTS) significantly inhibited the hypotensive and bradycardic response to 5 nmol of similarly administered donidine in both SHR and normotensive Sprague-Dawley rats. In SHR, a similar inhibition was observed after the 8-opiate receptor antagonist ICI 174864, but not after the ,u-receptor antagonist (3-funaltrexamine (both at 270 pmol, intra-NTS), whereas in normotensive Sprague-Dawley rats, ig-funaltrexamine, but not ICI 174864, was an effective inhibitor. The same pattern of differential inhibition was seen when clonidine was given i.v. and the opiate antagonists were given intracisternally in SHR and Sprague-Dawley rats. Intra-NTS microinjection of 280 fmol of ,B-endorphin caused hypotension and bradycardia, and these effects were similarly inhibited by ICI 174864 in SHR and by 18-funaltrexanuine in Sprague-Dawley rats. In SpragueDawley rats made hypertensive by chronic administration of deoxycorticosterone pivalate and salt, the hypotensive and bradycardic effects of intra-NTS clonidine were inhibited by ICI 174864, but not by (8-funaltrexamine, a pattern similar to that in SHR, but different from that in normotensive SpragueDawley rats. These results support the hypothesis that (.8 endorphin release and subsequent stimulation of opiate receptors in the NTS are involved in the cardiovascular effects of clonidine in rats. These results further suggest, however, that hypertension regulates the subtype of opiate receptors mediating these effects.Clonidine is a centrally acting antihypertensive agent with high affinity for a2-adrenergic receptors. Stimulation of a2-receptors in the brainstem by clonidine-like agents lowers arterial blood pressure (BP) and heart rate (HR) by decreasing sympathetic and increasing parasympathetic outflow to the periphery (1). Morphine and some opioid peptides cause similar effects by interacting with opiate receptors in the same brain region (2). Recent evidence indicates that the effects of central a2-receptor stimulation are due, in part, to

Melanocortin Antagonists Define Two Distinct Pathways of Cardiovascular Control by α- and γ-Melanocyte-Stimulating Hormones

“…Thus, one might speculate that the relative contributions to the net response of ␣-MSH and ␤-endorphin released from the same neuron may be regulated by the activity of an opiomelanocortin acetylase. The results of the microinjection experiments also indicate that, in agreement with earlier reports (Petty and De Jong, 1982;Mosqueda-Garcia and Kunos, 1987), ␤-endorphin microinjected at a low dose into the DVC causes hypotension and bradycardia. Unlike the similar effects of ␣-MSH, these effects are mediated by naloxone-sensitive opiate receptors, which are most likely of the -subtype (Mosqueda-Garcia and Kunos, 1987).…”

“…The results of the microinjection experiments also indicate that, in agreement with earlier reports (Petty and De Jong, 1982;Mosqueda-Garcia and Kunos, 1987), ␤-endorphin microinjected at a low dose into the DVC causes hypotension and bradycardia. Unlike the similar effects of ␣-MSH, these effects are mediated by naloxone-sensitive opiate receptors, which are most likely of the -subtype (Mosqueda-Garcia and Kunos, 1987). Thus, activation of the neural pathway projecting from the arcuate nucleus to the ipsilateral DVC can produce cardiovascular depressor effects via release of more than one product of the same precursor, which interact with distinct receptors.…”

“…In agreement with published observations (Petty and De Jong, 1982;Mosqueda-Garcia and Kunos, 1987;Li et al, 1996), unilateral microinjection of 1 pmol of ␤-endorphin into the DVC also caused long-lasting hypotension and bradycardia (Fig. 2).…”

“…1B). This dose of l-naloxone was found, in an earlier study, to cause near-maximal inhibition of the effects of ␤-endorphin microinjected into the DVC of anesthetized rats (Mosqueda-Garcia and Kunos, 1987). l-Naloxone did not modify the effects of ␣-MSH, indicating the lack of opiate receptor involvement.…”

Cardiovascular excitatory effects of adenosine in the nucleus of the solitary tract.

“…In addition to glutamate and adenosine, other agents including angiotensin, catecholamines, acetylcholine, and opioid peptides are known to reduce blood pressure and heart rate when microinjected into the NTS. 25 -39 - 41 Furthermore, the putative inhibitory neurotransmitter glycine also has been reported to exert hypotensive and bradycardic responses in the NTS 42 that in contrast to the present results, seemed to be mediated by cholinergic systems. 43 We attempted to elucidate whether some of these systems could also be involved in the final cardiovascular response of intra-NTS injections of adenosine.…”