Mechanism of cardiovascular effects of nociceptin microinjected into the nucleus tractus solitarius of the rat

Abstract

.62, and 1.25 mmol/l of nociceptin into the medial nucleus tractus solitarius (mNTS) elicited decreases in mean arterial pressure (11 Ϯ 1.8, 20 Ϯ 2.1, 21.5 Ϯ 3.1, and 15.5 Ϯ 1.9 mmHg, respectively) and heart rate (14 Ϯ 2.7, 29 Ϯ 5.5, 39 Ϯ 5.2, and 17.5 Ϯ 3.1 beats/min, respectively). Because maximal responses were elicited by microinjections of 0.62 mmol/l nociceptin, this concentration was used for other experiments. Repeated microinjections of nociceptin (0.62 mmol/l) into the mNTS, at 20-min intervals, did not elicit tachyphylaxis. Bradycardia induced by microinjections of nociceptin into the mNTS was abolished by bilateral vagotomy. The decreases in mean arterial pressure and heart rate elicited by nociceptin into the mNTS were blocked by prior microinjections of the specific ORL1-receptor antagonist [N-Phe 1 ]-nociceptin-(1-13)-NH2 (9 mmol/l). Microinjections of the ORL1-receptor antagonist alone did not elicit a response. Prior combined microinjections of GABA A and GABAB receptor antagonists (2 mmol/l gabazine and 100 mmol/l 2-hydroxysaclofen, respectively) into the mNTS blocked the responses to microinjections of nociceptin at the same site. Prior microinjections of ionotropic glutamate receptor antagonists (2 mmol/l NBQX and 5 mmol/l D-AP7) also blocked responses to nociceptin microinjections into the mNTS. These results were confirmed by direct neuronal recordings. It was concluded that 1) nociceptin inhibits GABAergic neurons in the mNTS, 2) GABAergic neurons may normally inhibit the release of glutamate from the terminals of peripheral afferents in the mNTS, and 3) inhibition of GABAergic neurons by nociceptin results in an increase in the release of glutamate in the mNTS, which in turn elicits depressor and bradycardic responses via activation of ionotropic glutamate receptors on secondary mNTS neurons. bradycardia; depressor responses; opioid peptides THE PRESENCE OF A NOVEL G-protein-coupled receptor [opioid receptor-like receptor (ORL1) or OP 4 receptor] throughout the central nervous system has been repeatedly demonstrated (1, 3, 6, 12, 18, 20 -22). There is a high sequence similarity of this receptor with other opioid receptors (e.g., -, ␦-, and -receptors) (3,6,21,36). Nociceptin (orphanin FQ) (4, 25, 26), a heptadecapeptide, has been demonstrated to be an endogenous ligand of ORL1 receptor because of its high and selective affinity for this receptor and a very poor affinity for -, ␦-, and -opioid receptors. One notable difference between other opioid receptor agonists (e.g., endomorphins, enkephalins, and dynorphin A) and nociceptin is that naloxone blocks the effects of these opioid receptor agonists but not those of nociceptin (4,5,13,16,29).The presence of an endogenous ligand for ORL1 receptors (nociceptin or orphanin FQ) has been demonstrated throughout the central nervous system, including the nucleus tractus solitarius (NTS) (10, 23, 35). There are very few reports in which the cardiovascular effects of ORL1 receptor activation by nociceptin in the medial nucleus tractus solitarius (m...

Cardiovascular responses elicited by a new endogenous angiotensin in the nucleus tractus solitarius of the rat

“…The mNTS sites eliciting depressor and bradycardic responses were identified by microinjections of L-Glu (5 mM) (8,39). The volume of all microinjections into the mNTS was 100 nl; the selection of this volume was based on our previous study (6). The volumes were pressure ejected and visually confirmed by the displacement of fluid meniscus in the barrel containing the solution using a modified binocular horizontal microscope with a graduated reticule in one eye piece.…”

“…immunoreactive for ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) has been demonstrated in the nucleus tractus solitarius (NTS) of the rat (1,24). It has recently been reported that bilateral microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the NTS attenuate the bradycardic responses to intravenous injections of phenylephrine (PE) (1).…”

“…It has recently been reported that bilateral microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the NTS attenuate the bradycardic responses to intravenous injections of phenylephrine (PE) (1). In another study, chronic immunoneutralization of endogenous brain ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) by intracerebroventricular injections of anti-ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) IgG in the hypertensive phenotype of the (mRen2)27 rat elicited antihypertensive effects (16). The medial subnucleus of the NTS (mNTS) has been reported to be the first site where peripheral baroreceptor, chemoreceptor, and cardiopulmonary afferents make their primary synapse (10,14,(33)(34)(35)39).…”

“…The medial subnucleus of the NTS (mNTS) has been reported to be the first site where peripheral baroreceptor, chemoreceptor, and cardiopulmonary afferents make their primary synapse (10,14,(33)(34)(35)39). The present investigation was undertaken to test the hypothesis that ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) exerts an excitatory effect on barosensitive mNTS neurons, causing the activation of sympathetic and parasympathetic pathways, which results in depressor and bradycardic responses.…”

Glutamatergic Inputs in the Hypothalamic Paraventricular Nucleus Maintain Sympathetic Vasomotor Tone in Hypertension

“…The following doses of the drugs were used: Kyn, 0.15 to 5 nmol/50 nL; AP5, 0.16 to 1.4 nmol/50 nL; CNQX, 0.22 to 1.8 nmol/50 nL; and gabazine, 0.3 to 10 nmol/50 nL. The microinjection doses for Kyn, 15,27 AP5, 15 CNQX, 29 and gabazine 30,31 were selected from previous studies and tested in the pilot experiments.…”