The effect of naloxone on blood pressure, heart rate, plasma catecholamines, renin activity and aldosterone following exercise in healthy males

There is evidence that endogenous opioids are involved in blood pressure regulation. In the present study the effect of naloxone on the cardiovascular, sympathoadrenomedullary and renin-aldosterone response to physical exercise was investigated in 8 healthy males. Each subject performed a submaximal work test twice, i.e. with and without naloxone. The test consisted of ergometer bicycling for 10 minutes on 50% of the maximal working capacity (MWC), immediately followed by 10 min on 80% of MWC. Ten minutes before exercise the subjects received in a single blind randomized order a bolus dose of naloxone (100 micrograms/kg) or a corresponding volume of the preservatives of the naloxone preparation (control) followed by a slow infusion of naloxone (50 micrograms/kg/h) or preservatives, respectively. Naloxone was without effect on the exercise-induced changes in systolic blood pressure, heart rate, plasma noradrenaline, renin activity and aldosterone, but the adrenaline response increased markedly. The present results indicate that opioid receptors are involved in the plasma adrenaline response to submaximal exercise, but not in the regulation of systolic blood pressure, heart rate, plasma noradrenaline, renin activity and plasma aldosterone.     

Possible role of an endogenous opioid in the antihypertensive action of propranolol in spontaneously hypertensive rats

The effect on systolic blood pressure and heart rate of the acute and chronic intraperitoneal (i.p.) administration of d- and dl-propranolol was investigated on unanesthetised spontaneously hypertensive rats. The effect of naloxone on the propranolol induced hypotension was also studied to test the hypothesis that the antihypertensive effect of propranolol involves the release of an endogenous opiate. On i.p. administration, 3 mg/kg d-propranolol was inactive; 3 and 30 mg/kg dl-propranolol decreased blood pressure and heart rate in a dose-dependent manner. When the rats were pretreated with 2 mg/kg naloxone i.p., the effect of propranolol on the blood pressure was nearly completely abolished, while that on the heart rate was only partially blocked. Chronic administration of dl-propranolol (30 mg/kg b.i.d.) to spontaneously hypertensive rats from the age of 6 weeks (prehypertensive phase) for 29 days prevented the development of hypertension while the rats treated with physiological saline for 29 days (control group) developed hypertension. Naloxone (2 mg/kg i.p.) administered on the 29th day to chronically treated rats induced a reversal of the propranolol action on systolic blood pressure and heart rate, i.e., blood pressure and heart rate increased. Naloxone had no such effect in the control group. We suggest that the release of an endogenous opioid contributes to the acute and chronic antihypertensive action of i.p. propranolol in spontaneously hypertensive rats and that the secretion of endogenous opioids participating in the control of cardiovascular functions is influenced by adrenergic mechanisms.     

Inhibition of an opioid-evoked vagal reflex in rats by naloxone,SMS 201-995 and ICI 154,129

Intravenous injection of opioid agonists in rats evokes a vagal reflex resulting in a fall in heart rate and blood pressure. Three opioid antagonists, naloxone, SMS 201-995, and ICI 154,129 were used to assess the nature of the opioid receptors that mediate the vagal reflex. The agonists used were morphine, Tyr-Pro-NMePhe-d-Pro-NH₂ (PLO17), and d-Ala²-Leu⁵-enkephalin (DADL). At challenge doses of morphine, PLO17, and DADL at five times the ED50 for bradycardia, the naloxone ED50 for DADL was nine times greater than that for morphine and PLO17. The pA₂ value of naloxone against DADL was significantly less than that for morphine and PLO17. The antagonist properties of SMS 201-995 were similar to those of naloxone. ICI 154,129, a putative delta receptor antagonist, was not, however, selective in its antagonism of opioid bradycardia. Both SMS 201-995 and ICI 154,129, when injected alone, produced changes in heart rate and blood pressure. The cardiovascular actions of the peptide antagonists were not affected by naloxone hydrochloride at doses up to 4 mg/kg i.v.     

Endorphins stimulate normal human peripheral blood lymphocyte natural killer activity

Opioid peptides are present in peripheral blood, and may bind to human lymphocytes. In order to determine their influence on human lymphocytes we studied the effect of endogenous opioid peptides on human lymphocyte natural killer function. Beta-endorphin and several analogues (i.e., gamma-endorphin) are shown to enhance human peripheral blood natural killer function. The enhancement of natural killing by these opioid peptides was dose-dependent and naloxone (an opiate antagonist) reversible. In studying various analogues of beta-endorphin, beta-lipotropin and gamma-endorphin were approximately 3-5 times more effective at enhancing peripheral blood NK function than Leu-enkephalin and -endorphin. In addition, we observed that naloxone reversed human fibroblast interferon mediated enhancement of human blood lymphocyte natural killer function. These observations suggest that circulating endogenous opioid peptides may have a physiologic role in regulating human blood lymphocyte natural killing.     

The effect of opiate receptor ligands on emotional cardiovascular reactions in lower primates

Intravenous naloxone injection (0.1 mg/kg) facilitated blood pressure increase in response to conditioned sound stimulus followed by electrocutaneous shock in conscious chair-restrained baboons (Papio hamadryas). Naloxone at a dose of 1.0 mg/kg had an opposite effect and led to the decrease in blood pressure and heart rate in conditioned fear reflex. Naloxone microinjections (50 microM) into the periventricular hypothalamus led to a significant diminution of blood pressure and heart rate increment in response to electrocutaneous shock; naloxone microinjections into tractus solitarius nuclei suppressed blood pressure and heart rate reactions both to conditioned (sound) and unconditioned (electrocutaneous shock) stimuli. Microinjections of equimolar morphine quantities in these brain regions facilitated such reactions. It is concluded that endogenous opioid system participates in the formation of cardiovascular reactions to emotional stimuli in monkeys, with multiple opioid receptors of periventricular hypothalamus and tractus solitarius nuclei involved in the generation of such reactions.     

Cardiovascular responses to opioid agonists injected into the nucleus of tractus solitarius of anesthetized cats

It has been proposed that various opiate receptor subtypes mediate different cardiovascular responses to centrally administered opioids. We evaluated this hypothesis in chloralose-urethane anesthetized cats by monitoring the cardiovascular and respiratory responses to relative mu [morphine, morphiceptin, D-Ala2, MePhe4, Gly-ol5 enkephalin (DAGO)] and delta [D-Ala2, D-Leu5enkephalin (DADL)] agonists microinjected (0.5 ul/kg) into the caudal region of the Nucleus of Tractus Solitarius (NTS). Dynorphin (1-13), an endogenous opioid which exhibits selective affinity towards the kappa receptor, was also tested. Dynorphin at a dose of 50 nMol/kg did not alter cardiovascular or respiratory variables. Morphine (10-54 nMol/kg) and DAGO (50 nMol/kg) had no effect on blood pressure, heart rate or respiratory rate; morphiceptin (100-320 nMol/kg) caused tachycardia only at the highest dose. DADL (10-100 nMol/kg) elicited a dose-dependent depression of blood pressure. High doses of DADL depressed heart rate and respiratory rate. The depressor effects of DADL were reversed by low doses of naloxone (0.1 mg/kg). This dose of naloxone also elicited pressor responses in cats treated with the other opioids and reversed the morphiceptin-induced tachycardia. These data indicate that opioid agonists differ with regard to their cardiovascular and respiratory effects following microinjection into the NTS of anesthetized cats, with the delta agonist DADL showing greatest activity.     

Paradoxical effects of intracerebroventricular low-dose opioid antagonists in SHR with chronic pain.

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.     

Failure of naloxone to influence surgical reversal of two-kidney, one-clip hypertension in the rat

The rapid fall in blood pressure after removal of the constricting clip in two-kidney one-clip (2K-1C) hypertension in the rat is not fully explained by inhibition of the renin-angiotensin system or change in sodium balance. It has been postulated that compounds released in the renal venous effluent following unclipping of 2K-1C rats have a central opiate-like action and endogenous opioids are recognized to have profound hypotensive properties. To investigate this, we removed the clip from, or performed a sham operation in, early phase (less than 6 weeks) 2K-1C hypertensive rats during an infusion of naloxone, an opioid antagonist, or vehicle alone. The infusion of naloxone did not affect the pattern of blood pressure fall in either unclipped or sham-operated rats. Both naloxone-treated and control groups were similarly normotensive at 24 hr postoperation, the MAP being significantly lower than in the sham-operated groups, which regained previously hypertensive levels. Heart rate was unchanged 24 hr postoperatively in all groups. Morphine-induced bradycardia and hypotension were significantly reduced by naloxone infusion. Thus, naloxone infusion had no effect on blood pressure or heart rate in either the sham-operated or the unclipped groups, indicating that endogenous opioids do not have a major role in the reversal of renovascular hypertension under these circumstances.     

Effects of naloxone and fentanyl in acutely decerebrated dogs

Cardiovascular, respiratory and analgesic effects of fentanyl and naloxone were studied in normotensive acutely decerebrated dogs. Naloxone (1 mg/kg, i.v.) increased skin twitch reflex latency, mean blood pressure, pulse pressure, respiratory rate and minute volume. Fentanyl (50 μg/kg, i.v.) decreased heart rate and blood pressure while the animals were artificially ventilated. The skin twitch reflex latency was not significantly altered. Nine minutes later, naloxone (1 mg/kg, i.v.) was administered and the fentanyl-induced cardiovascular depression was reversed above the control level. The skin twitch reflex latency remained unchanged. These findings give further evidence that the endogenous opioid system plays an important role in the brainstem control of circulation and respiration. The mechanism of the anomalous analgesic response of the acutely decerebrated dog requires further investigation.     

Failure of reversal of cardiovascular responses of clonidine by centrally administered naloxone in anaesthetised rats

Central effects of naloxone on the cardiovascular responses of centrally administered clonidine were studied in anaesthetised normotensive, renal DOCA-salt hypertensive and morphine dependent rats. Clonidine (5 micrograms/ICV) produced significant decrease in blood pressure and heart rate in all the groups of rats in a dose dependent manner. Naloxone (2 micrograms/ICV) failed to reverse the responses of clonidine in all the rat groups. In morphine dependent normotensive and morphine dependent renal DOCA-salt hypertensive rats, the responses of clonidine were further enhanced in the presence of naloxone. Our observations clearly indicate that clonidine does not influence endogenous opioid system for producing cardiovascular effects.     

Carotid baroreflex sensitivity at rest and during exercise is not influenced by opioid receptor antagonism

Physical effort involves, along with an increase in the plasma concentration of beta-endorphin, profound cardiovascular adaptations. The aim of the present study was to investigate with the use of the variable neck chamber technique, the influence of the endogenous opioids on the carotid baroreflex control of blood pressure and heart rate at rest as well as during exercise. Ten normal volunteers exercised in the supine position up to 33% and 66% of their maximal exercise capacity and received, in a randomized double-blind cross-over protocol, either saline or naloxone (10 mg intravenously, followed by a continuous infusion of 10 mg.h-1). During exercise a progressive attenuation of the carotid baroreceptor reflex control of blood pressure and heart rate was noted. However, neither at rest nor during exercise, did opioid antagonism influence the carotid baroreceptor control of blood pressure and heart rate. Intra-arterial pressure and heart rate also remained unaffected. In contrast, both at rest and during exercise, naloxone administration produced a significant increase in the plasma concentration of cortisol. The latter suggests that in vivo the opioid receptors were effectively antagonized. In conclusion the present study confirms that opioids play only a minor role in cardiovascular homeostasis at rest. In addition, this study demonstrates that they are not involved in the cardiovascular adaptation to exercise, nor in the exercise-related attenuation of the carotid baroreceptor control of pressure and heart rate.     

Cardiovascular effects of intraventricular injection of FMRFamide, Met-enkephalin and their common analogues in the rat

The molluscan neuropeptide, Phe-Met-Arg-Phe-NH2 (FMRFamide), the mammalian opioid peptide met-enkephalin, and their common analogues, met-enkephalin-Arg6-Phe7 (YGGFMRF) and Tyr-Gly-Gly-Phe-Met-Arg-Phe-amide (YGGFMRFamide), were injected into the lateral ventricle of the rat; the cardiovascular effects were studied. FMRFamide caused a rapid, transient elevation in blood pressure accompanied by a great increase in pulse pressure. These effects were followed by secondary increases in blood and pulse pressures. Met-enkephalin produced an initial reduction in blood pressure which was followed by a gradual increase at the higher of two test doses (300 nmole). Injection of YGGFMRF resulted in a gradual increase in blood pressure. This response resembled that to met-enkephalin. The initial response to YGGFMRFamide was similar to that to FMRFamide: increases in both blood and pulse pressures after injection. However, the secondary effect of YGGFMRFamide, a prolonged reduction in blood pressure, was not produced by FMRFamide. These results suggest that the initial excitatory cardiovascular responses may be due to the presence of the C-terminal amide. All of the cardiovascular effects of injecting these peptides into the lateral ventricle were abolished by pre-treatment with naloxone in a dose that, itself, produced no cardiovascular changes. In conclusion, these peptides seem to act via the naloxone sensitive opiate receptors in the rat brain.     

An opioid basis for early-phase isoflurane-induced hypotension in rats

This study was conducted to more clearly delineate the possible role of endogenous opioid receptors and opioid peptides in general anesthesia-associated hypotension in rats. Exposure to 2% isoflurane in oxygen produced a triphasic change in mean arterial pressure (MAP), including an early phase in which MAP fell by -28.4 +/- 2.2%. The magnitude of this early-phase hypotension was attenuated in rats pretreated with intravenous (i.v.) mu-subtype-selective doses of either naloxone or methylnaloxone but not central doses of the selective mu-opioid antagonist beta-funaltrexamine. This early hypotensive phase was also reduced following i.v. pretreatment with antiserum against methionine-enkephalin but not beta-endorphin. These findings suggest that early-phase isoflurane-induced hypotension may be due to activation of peripheral mu-opioid receptors by an endogenous opioid peptide, possibly related to methionine-enkephalin.     

Effect of naloxone in hypotension caused by acute blood loss in Papio hamadryas baboons

Naloxone or physiological solution were injected in different doses to 11 baboons (Papio hamadryas) weighing 7-8 kg after bloodletting in a volume of 40% of the total amount of the blood. Naloxone effectively raised (in all the doses) the arterial blood pressure which dropped after bloodletting. The action of naloxone injected in small doses was more pronounced and had unique time parameters. Besides, the respiratory rate was also increased. Injection of nalorphine in a dose of 1 mg/kg produced a similar but a more demonstrable action as compared with naloxone in a dose of 1 mg/kg. A conclusion is made about the possibility of using the antagonists of opioid peptides on a clinical basis for the treatment of shock conditions. An assumption of an inconclusive role played by the subtypes of opiate receptors in the formation of shock conditions is also confirmed.     

Changes in the autonomic balance of the regulation of the rate of heart contractions during physical loading in chronic suppression or potentiation of the endogenous opioidergic system in rats

The influence of endogenous opioid system on the rat's mean blood pressure (BP) and heart rate (HS) has been studied under the chronic infusion of the opioid receptor antagonist naloxone (1 mg/kg intraperitoneally, twice a day, during 6 days) or an inhibitor of captorile enkephalinases (20 mg/kg subcutaneously). Naloxone caused a significant decrease and captorile--increase of maximum meanings of HR during exercises (the running on the treadmill during 3.5 min by the velocity of 30 m/min), both compounds didn't exert a considerable effect on BP at rest and during exercises. It has been concluded that the endogenous opioid system plays an important role in the autonomic HR regulation during exercise.     

Effect of vasopressin and naloxone alone and in combination on cortisol secretion after dexamethasone pretreatment

In order to further examine the possible role of endogenous opioid peptides and vasopressin in the phenomenon of dexamethasone nonsuppression, we studied the effect of naloxone, vasopressin, and vasopressin-naloxone combination on cortisol secretion following dexamethasone pretreatment. Nine healthy males were given 1 mg dexamethasone at 23.00 h. The following day starting at 12.30 h and at 90-min intervals they received intravenously naloxone (0.2 mg/kg), arginine vasopressin 3 units, or the two drugs combined. The order of drug administration was counterbalanced using a Latin square design. Blood samples were drawn at 15-min intervals, and plasma aliquots were assayed for cortisol and dexamethasone. Naloxone failed to induce an escape from dexamethasone suppression. Four of the 9 subjects responded with an escape from dexamethasone suppression in response to vasopressin alone. The observed variability in response to vasopressin was unrelated to dexamethasone plasma levels but was associated with a decrease in systolic blood pressure. Peak cortisol levels were lowest in response to naloxone and highest in response to vasopressin. There was no evidence of an increased cortisol response to the coadministration of naloxone with vasopressin compared to vasopressin alone. These results fail to implicate an opioidergic mechanism in the pathophysiology of dexamethasone nonsuppression.     

Participation of endogenous opioid peptides in the pathogenesis of motion sickness

Investigations were performed with 19 healthy male volunteers to specify a possible role of endogenous opioid peptides in the pathogenesis of motion sickness. For this purpose the test subjects were administered naloxone, a specific antagonist of opiates and opioids, before rotation and during rotation in a BU-4 armchair at a rate of 30 rpm. In addition, the content of beta-endorphin in blood plasma was measured. It was discovered that naloxone exerts both prophylactic and therapeutic effects as regards the simulated motion sickness. In this respect it was more efficacious than the reference drug scopolamine. After rotation there was a significant increase in the beta-endorphin content in the blood plasma of the test subjects. It is assumed that endogenous opioid peptides (in particular beta-endorphin) may be directly involved in the genesis of vestibulo-vegetative disorders in motion sickness.     

Reversal of morphine, methadone and heroin induced effects in mice by naloxone methiodide

Opioid overdose, which is commonly associated with opioid induced respiratory depression, is a problem with both therapeutic and illicit opioid use. While the central mechanisms involved in the effects of opioids are well described, it has also been suggested that a peripheral component may contribute to the effects observed. This study aimed to further characterise the effects of the peripherally acting naloxone methiodide on the respiratory, analgesic and withdrawal effects produced by various opioid agonists. A comparison of the respiratory and analgesic effects of morphine, methadone and heroin in male Swiss-Albino mice was conducted and respiratory depressive ED(80) doses of each opioid determined. These doses (morphine 9 mg/kg i.p., methadone 7 mg/kg i.p., and heroin 17 mg/kg i.p.) were then used to show that both naloxone (3 mg/kg i.p.) and naloxone methiodide (30-100 mg/kg i.p.) could reverse the respiratory and analgesic effects of these opioid agonists, but only naloxone precipitated withdrawal. Further investigation in female C57BL/6J mice using barometric plethysmography found that both opioid antagonists could reverse methadone induced decreases in respiratory rate and increases in tidal volume. Its effects do not appear to be strain or sex dependent. It was concluded that naloxone methiodide can reverse the respiratory and analgesic actions of a variety of opioid agonists, without inducing opioid withdrawal.     

Systemic methionine-enkephalin evokes cardiostimulatory responses in the human

The cardiovascular effects of bolus doses of methionine-enkephalin (Met5-ENK) (1 to 100 micrograms/kg) were studied in 9 subjects in whom, at cardiac catheterization for evaluation of chest pain, patent coronary arteries were found. Met5-ENK produced a simultaneous increase in blood pressure and heart rate beginning within 20 sec, reaching maximal values between 30 and 40 sec, and then terminating by 60 sec. Heart rate, systolic, diastolic, and mean arterial blood pressures increased significantly (p less than 0.0005); pulse pressure remained unchanged. Positive dose-effect relationships were observed for heart rate (p less than 0.002), systolic, diastolic, and mean arterial blood pressures (p less than 0.05). Naloxone (0.5 mg/kg), given to 4 subjects, prevented the heart rate and blood pressure changes associated with Met5-ENK administration, demonstrating that the cardiovascular changes were mediated by opiate receptors. Subjects also described cutaneous paresthesias which were not prevented by naloxone pretreatment. These data suggest a role for peripheral enkephalins in cardiovascular regulation.     

Regulation of hypophysial secretion by endogenous opiates: Humoral endorphin stimulates the release of growth hormone

Humural endorphin, a recently discovered endogenous opioid factor stimulates the release of growth hormone and, to some extent of prolactin, similarly to other endogenous (enkephalin, β-endorphin) and exogenous (morphine) opiates. This stimulatory effect is dose-dependent with peak values at 30 minutes following intraventricular injection to newborn rats. However, in contrast to the other opioid ligands, the effect of humoral endorphin is not blocked in a dose-dependent fashion by naloxone, the potent opiate antagonist. Thus, while moderate doses of naloxone partially inhibit the stimulatory effect, higher doses which completely block morphine, enkephalin and β-endorphin, are ineffective in antagonizing humoral endorphin. This peculiar interaction between naloxone and humoral endorphin resembles the effect of the opiate antagonist on spontaneous release of growth hormone and prolactin, suggesting the involvement of humoral endorphin in the physiological regulation of hypophysial secretion.