The decompensatory phase of acute hypovolaemia in rabbits involves a central δ1-opioid receptor

doi:10.1016/0014-2999(94)90582-7

European Journal of Pharmacology

Volume 252, Issue 1, 24 January 1994, Pages 113-116

https://doi.org/10.1016/0014-2999(94)90582-7 Get rights and content

Abstract

Graded caval occlusion in conscious rabbits caused a biphasic response. Phase I was characterized by a fall in conductance so that arterial pressure was maintained. When cardiac output had fallen to 69 ± 2% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a like-threatening level (< 40 mm Hg). Centrally administered δ-opioid receptor antagonists prevented the occurence of phase II. The relative order of potency was 7-benzyl-idenenaltrexone (BNTX, δ₁-selective) > N,N-diallyl-Tyr-Aib-Phe-Leu-OH (ICI 174 864) > naltrindole (δ₂-selective). It is concluded that a central δ₁-opioid receptor is involved in the onset of the second decompensatory phase of the haemodynamic response to haemorrhage.

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Cited by (28)

Hypovolemic hemorrhage induces Fos expression in the rat hypothalamus: Evidence for involvement of the lateral hypothalamus in the decompensatory phase of hemorrhage
2016, Neuroscience
Citation Excerpt :
These findings extend an earlier report that hemorrhage induces Fos expression by neurons in the arcuate nucleus, including neurons that synthesize pro-opiomelanocortin (POMC), the precursor for β-endorphin, ACTH, α-melanocyte-stimulating hormone and other neuropeptides (Göktalay et al., 2006). This earlier study was predicated on evidence that opioid receptor antagonists inhibit hemorrhagic hypotension when administered i.v. (Faden and Holaday, 1979), i.c.v. (Ludbrook and Ventura, 1994) or directly into the vlPAG (Cavun et al., 2001) and that arcuate POMC neurons are a principal source of the extrinsic opioid innervation of the vlPAG (O’Donohue and Dorsa, 1982; Chronwall, 1985; Cone, 2005). Hemorrhage also elevated POMC mRNA levels in the arcuate nucleus, again, indicating that hemorrhage activates POMC neurons (Göktalay et al., 2006).
This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100 g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 μl or 0.3 μl) or cobalt chloride (5 mM; 0.3 μl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage.
Role of lateral parabrachial opioid receptors in exercise-induced modulation of the hypotensive hemorrhage response in conscious male rats
2012, Behavioural Brain Research
Citation Excerpt :
Previous literature has shown that opioids are involved in the onset of HEM-induced sympatho-inhibition in multiple regions of the CNS. In the periaqueductal grey, for example, delta-opioid receptor antagonism prevents the sympathoinhibitory phase of HEM in conscious rabbits [46]. Administration of μ-opioid [21] and kappa-opioid [20] receptor antagonists into the 4th ventricle also prevent the onset of hemorrhagic hypotension in conscious rabbits, suggesting the possibility that more than a single type of opioid receptor is involved in mediating the reflex bradycardia and hypotension during severe HEM.
Some of the benefits of exercise appear to be mediated through modulation of neuronal excitability in central autonomic control circuits. Previously, we identified that six weeks of voluntary wheel running had a protective effect during hemorrhage (HEM), limiting both the hypotensive phase of HEM and enhancing recovery. The present study was undertaken to evaluate the role of opioid release in the lateral parabrachial nucleus (LPBN) on the response to severe HEM in chronically exercised (EX, voluntary) versus sedentary (SED) controls. Male Sprague Dawley rats were allowed either free access to running wheels (EX) or normal cage conditions (SED). After 6 weeks of “training” animals were instrumented with a bilateral cannula directed toward the dorsolateral pons and arterial catheters. After a recovery period, animals underwent central microinjection of either vehicle (VEH; n = 3/group) or the opioid receptor antagonist naloxone (NAL; n = 6/group) followed by withdrawal of 30% of their total estimated blood volume. Following VEH injection, the drop in MAP during and following HEM was significantly attenuated in the EX vs SED animals. Alternatively, NAL microinjection in the dorsolateral pons (20 μM, 200–500 nl) reversed the beneficial effect of EX on the HEM response. NAL microinjection in SED rats did not significantly alter the response to HEM. These data suggest chronic voluntary EX has a beneficial effect on the autonomic response to severe HEM which is mediated, in part, via EX-induced plasticity of the opioid system within the dorsolateral pons.
Hemorrhage activates proopiomelanocortin neurons in the rat hypothalamus
2006, Brain Research
Citation Excerpt :
The initial evidence for this was a report by Faden and Holaday (1979) published more than 25 years ago that iv naloxone injection inhibited hemorrhagic hypotension in conscious rats. Subsequent studies showed that naloxone prevented the decline in sympathetic nerve activity evoked by hemorrhage in conscious rabbits (Burke and Dorward, 1988; Hasser and Schadt, 1992; Yamashita et al., 1996) and that both naloxone (Eijgelshoven et al., 1991; Evans et al., 1989) and a delta-1 opioid receptor antagonist (Ludbrook and Ventura, 1994) were effective following icv or intracisternal administration. In an earlier study, we also found that both naloxone and the delta opioid receptor antagonist naltrindole blocked hemorrhagic hypotension and bradycardia when injected directly into the ventrolateral column of the midbrain periaqueductal gray region (vlPAG) (Cavun et al., 2001).
Severe blood loss lowers arterial pressure through a central mechanism that is thought to include opioid neurons. In this study, we investigated whether hemorrhage activates proopiomelanocortin (POMC) neurons by measuring Fos immunoreactivity and POMC mRNA levels in the medial basal hypothalamus. Hemorrhage (2.2 ml/100 g body weight over 20 min) increased the number of Fos immunoreactive neurons throughout the rostral–caudal extent of the arcuate nucleus, the retrochiasmatic area and the peri-arcuate region lateral to the arcuate nucleus where POMC neurons are located. Double label immunohistochemistry revealed that hemorrhage increased Fos expression by β-endorphin immunoreactive neurons significantly. The proportion of β-endorphin immunoreactive neurons that expressed Fos immunoreactivity increased approximately four-fold, from 11.7 ± 1.4% in sham-operated control animals to 42.0 ± 5.2% in hemorrhaged animals. Hemorrhage also increased POMC mRNA levels in the medial basal hypothalamus significantly, consistent with the hypothesis that blood loss activates POMC neurons. To test whether activation of arcuate neurons contributes to the fall in arterial pressure evoked by hemorrhage, we inhibited neuronal activity in the caudal arcuate nucleus by microinjecting the local anesthetic lidocaine (2%; 0.1 or 0.3 μl) bilaterally 2 min before hemorrhage was initiated. Lidocaine injection inhibited hemorrhagic hypotension and bradycardia significantly although it did not influence arterial pressure or heart rate in non-hemorrhaged rats. These results demonstrate that hemorrhage activates POMC neurons and provide evidence that activation of neurons in the arcuate nucleus plays an important role in the hemodynamic response to hemorrhage.
The hypotension evoked by visceral nociception is mediated by delta opioid receptors in the periaqueductal gray
2004, Brain Research
Citation Excerpt :
The present findings extend earlier evidence that lidocaine [8] and naltrindole [9] administration into the vlPAG delays the onset and reduces the magnitude of hemorrhagic hypotension. Earlier investigations had shown the decompensatory phase of hemorrhage to be attenuated by intraventricular administration of naloxone [47] and delta receptor antagonists [30]. We found that naltrindole injection into the vlPAG attenuated the decompensatory phase of hemorrhage at doses ranging from 0.2 to 20 nmol; the dose used in the present study, 2 nmol, was approximately the ED50[9].
This study tested the hypothesis that the ventrolateral column of the midbrain periaqueductal gray (vlPAG) region mediates the hypotension and bradycardia evoked by visceral nociception. To test this, the local anesthetic lidocaine (2%; 0.5 μl) was microinjected into the vlPAG of halothane-anesthetized rats bilaterally and visceral nociception was induced 2 min later by injecting 5% acetic acid (0.5 ml) intraperitoneally. Acetic acid injection caused an abrupt fall in arterial pressure (−12.2±2.1 mm Hg) and heart rate (−37±93 bpm) lasting approximately 15 min. Lidocaine injection into the vlPAG prevented the fall in arterial pressure and heart rate completely. Cobalt chloride (5 mM; 0.2 or 0.5 μl) injection into the vlPAG also prevented nociceptive hypotension but it did not affect the fall in heart rate significantly. Lidocaine pretreatment also inhibited the depressor response caused by intramuscular formalin (5%; 0.2 ml) administration, a model of deep somatic nociception, although it did not prevent the response completely. To determine if opioid receptors mediate the response, selective mu, delta or kappa opioid receptor antagonists were microinjected into the vlPAG 5 min before intraperitoneal (ip) acetic acid administration. Naltrindole, a delta receptor antagonist, inhibited the response significantly but mu and kappa antagonists were completely ineffective. Lidocaine and naltrindole had no effect when injected into the dorsolateral PAG and did not influence cardiovascular function when injected into the vlPAG of saline treated control animals. These data support the hypothesis that the vlPAG mediates the depressor response evoked by visceral nociception and indicate that delta opioid receptors participate in the response.
C1 adrenergic neurons are contacted by presynaptic profiles containing delta-opioid receptor immunoreactivity
2002, Neuroscience
Ligands of the δ-opioid receptor tonically influence sympathetic outflow. Some of the actions of δ-opioid receptor agonists may be mediated through C1 adrenergic neurons in the rostral ventrolateral medulla. The goal of this study was to determine whether C1 adrenergic neurons or their afferents contain δ-opioid receptors. Single sections through the rostral ventrolateral medulla were labeled for δ-opioid receptor using the immunoperoxidase method and the epinephrine synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT) using the immunogold method, and examined at the light and electron microscopic level. Few (∼5% of 903) profiles dually labeled for PNMT and δ-opioid receptor were detected; most of these were dendrites with diameters <1.5 μm. δ-Opioid receptor immunoreactivity was affiliated with multivesicular bodies in dually labeled perikarya, whereas δ-opioid receptor immunoperoxidase labeling appeared as isolated clusters within both singly and dually labeled dendrites. The majority (∼83% of 338) of δ-opioid receptor-immunoreactive profiles were axons and axon terminals. δ-Opioid receptor-immunoreactive terminals averaged 0.75 μm in diameter, contained numerous large dense-core vesicles and usually formed appositions or asymmetric (excitatory-type) synapses with their targets. The majority (>50% of 250) of δ-opioid receptor-immunoreactive axons and axon terminals contacted PNMT-immunoreactive profiles. Most of the contacts formed by δ-opioid receptor-immunoreactive profiles (∼75% of 132) were on single-labeled PNMT-immunoreactive dendrites with diameters <1.5 μm.
The prominent localization of δ-opioid receptors to dense-core vesicle-rich presynaptic profiles suggests that δ-opioid receptor activation by endogenous or exogenous agonists may modulate neuropeptide release. Furthermore, the presence of δ-opioid receptors on axon terminals that form excitatory-type synapses with PNMT-immunoreactive dendrites suggests that δ-opioid receptor ligands may modulate afferent activity to C1 adrenergic neurons. The observation that some PNMT-immunoreactive neurons contain δ-opioid receptor immunoreactivity associated with multivesicular bodies and other intracellular organelles suggests that some C1 adrenergic neurons may present, endocytose and/or recycle δ-opioid receptors.
Morphine blocks the bradycardia associated with severe hemorrhage in the anesthetized rat
1997, Brain Research
Progressive hemorrhage in the absence of tissue injury produces a biphasic response: an initial tachycardia, vasoconstriction and maintenance of arterial blood pressure by the baroreflex, followed by bradycardia, vasodilatation and hypotension due to the activation of a second ‘depressor’ reflex. The present study has investigated the effect of morphine (a μ-opioid receptor agonist) on the cardiac chronotropic response to a progressive hemorrhage at 2% total estimated blood volume (BV) min⁻¹ in the anesthetized rat. In control rats (20 μl saline intracerebroventricularly, i.c.v.) heart period initially decreased significantly (P < 0.05) by a maximum of 5.4 ± 0.8 ms from a baseline of 147.3 ± 2.2 ms after a blood loss of 8.3 ± 1.5% BV, and then increased significantly by a maximum of 43.0 ± 5.5 ms above the baseline after the loss of 34.5 ± 1.6% BV. Blood pressure was initially maintained and then fell during the hemorrhage. The increase in heart period was prevented by treatment with morphine (10 μg i.c.v.), and the fall in blood pressure delayed significantly. These effects of morphine were prevented by pretreatment with naloxone (20 μg i.c.v.). Intravenous (i.v.) administration of morphine (10 μg) had no effect on the response to hemorrhage. However, a clinically relevant dose of 0.5 mg · kg⁻¹ morphine (i.v.) abolished the bradycardia and delayed the fall in blood pressure associated with hemorrhage. These results indicate that morphine, acting on central nervous opioid receptors, can abolish the bradycardia and delay the hypotension associated with progressive hemorrhage, a pattern of response reminiscent of the effects of musculo-skeletal injury on the response to blood loss.

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Short communicationThe decompensatory phase of acute hypovolaemia in rabbits involves a central δ1-opioid receptor

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Role of central opiate receptor subtypes in the circulatory responses of awake rabbits to graded caval occlusions

J. Physiol.

Confounding factors attending the use of intrapericardial procaine to block cardiac afferents in conscious rabbits

Am. J. Physiol.

Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5′-isothiocynate: evidence for delta receptor subtypes

J. Pharmacol. Exp. Ther.

On making multiple comparisons in clinical and experimental pharmacology and physiology

Clin. Exp. Pharmacol. Physiol.

Short communication
The decompensatory phase of acute hypovolaemia in rabbits involves a central δ₁-opioid receptor

Differential antagonism of opioid delta antinociception by [D-Ala²,Leu⁵,Cys⁶]enkephalin and naltrindole 5′-isothiocynate: evidence for delta receptor subtypes