Activation Of Opioid System Research Articles

Opioid Peptide Modulation of Circulatory and Endocrine Response to Mental Stress in Humans

Fontana, F., P. Bernardi, E. Merlo Pich, S. Boschi, R. De Iasio, S. Spampinato and G. Grossi. Opioid peptide modulation of circulatory and endocrine response to mental stress in humans. Peptides 18(2) 169–175, 1997.—Healthy subjects were classified according to their percent increase in systolic blood pressure (SBP) after mental arithmetic test (MAT) as low (ΔSBP 9.3–15.1%, n = 15) and high (ΔSBP 35.1–45.4%, n = 15) responders. During MAT, low responders showed significantly (p < 0.01) increased plasma levels of β-endorphin, cortisol, catecholamines, and atrial natriuretic factor (ANF) and decreased levels of endothelin-1, whereas high responders showed increased (p < 0.01) levels of Met-enkephalin, dynorphin B, and catecholamines. Pretreatment with naloxone hydrochloride enhanced (p < 0.01) SBP, heart rate, noradrenaline, cortisol, and endothelin-1 levels, and reduced (p < 0.01) ANF in low responders in response to MAT, whereas it decreased (p < 0.01) hemodynamic parameters, noradrenaline, and endothelin-1 in high responders. The individual differences in hemodynamic and endocrine responses to MAT may depend on a different activation of the endogenous opioid system.

Antidepressant-like effects of CCK B receptor antagonists: involvement of the opioid system

RB 101 ( N-[( R,S)-2-benzyl-3-[( S)-2-amino-4-methylthiobutyldithio]-1-oxopropyl]- l-phenylalaninebenzyl ester), a systemically active inhibitor of enkephalin catabolism, has been shown to elicit antidepressant-like effects in mice, both in the forced-swimming and in the conditioned suppression of the mobility tests. The same type of response has been also observed following administration of the cholecystokinin CCK B receptor antagonist L-365,260 ((3 R)-(+)- N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl)-3-methylphenylurea). Interestingly, the δ-opioid receptor antagonist naltrindole (17-cyclopropylmethyl-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7,2′-3′-indolomorphinan) blocks the effect of both RB 101 and L-365,260 in the conditioned suppression of the motility test. In this work we have investigated the involvement of the opioid system in the antidepressant response to the CCK B receptor antagonist L-365,260 in the forced-swimming test in mice. The effect of L-365,260 was decreased by the δ-opioid receptor antagonist naltrindole. Furthermore, the CCK B receptor agonist, BC 264 (Boc-Tyr(OSO 3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH 2), blocked the antidepressant-like effect of RB 101 while CCK-8 (H-Asp-Tyr(OSO 3H)-Met-Gly-Trp-Met-Asp-Phe-NH 2) enhanced the effect of this drug, probably through stimulation of central CCK A receptors, since the CCK A receptor antagonist devazepide ((3 S)-(−)-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl)-1 H-indole-2-carboxamide) abolished the CCK-8-induced potentiation of the RB 101 effect. In addition, RB 101 enhanced the effect of L-365,260. Such an effect was blocked by the δ-opioid receptor antagonist naltrindole. These data further support the involvement of opioid receptors in the antidepressant-type effect induced by CCK B receptor blockers and support the hypothesis of a regulatory role of CCK in the activity of the endogenous opioid system. As in other experimental paradigms, CCK A and CCK B receptor stimulation appears to have opposite effects in modulating opioidergic activity.

Activation of Different Opioid Systems by Muscle Activity and Exercise

Many positive effects of exercise have been ascribed to the exercise-induced activation of endogenous opioid systems. The hypothesis that different opioid peptides and receptors are involved in the cardiovascular, behavioral, and analgesic responses and that opioid-mediated effects of muscle exercise are triggered by activation of mechanosensitive muscle nerve afferents is reviewed.

P.4.016 - Effects of μ and κ opioid agonists on the cholecystokinin-induced activation of opioid system in isolated guinea-pig ileum

P.4.016 - Effects of μ and κ opioid agonists on the cholecystokinin-induced activation of opioid system in isolated guinea-pig ileum

Hypoxia decreases opioid delta receptor expression in mouse brain.

Delta opioid receptor activation is protective during hypoxic injury. Many adaptive responses occur during exposure to hypoxia to facilitate survival. It is possible that increased activity of the delta opioid receptor system is one such adaptation. We tested the hypothesis that mice exposed to prolonged hypoxia have increased expression of the delta opioid receptor in brain tissue. Prolonged exposure to hypoxia (9% oxygen, balance nitrogen) continuously for seven days selectively decreased delta opioid receptor expression in mouse brain homogenate. The same hypoxic treatment had no effects on either mu or kappa opioid receptor expression, indicating that this response was not due to non-selective degradation of protein. Shorter term hypoxic treatments (one day and three days) did not induce changes in delta opioid receptor expression in whole brain homogenate. Binding assays were also conducted in grossly dissected brain regions (cortex, midbrain, hindbrain) to determine whether the shorter term treatments would induce changes in receptor expression in more discrete areas. No consistent changes in delta opioid receptor expression were detected in these brain regions. These data demonstrate that opioid delta receptors are hypoxia sensitive and may be a part of an adaptive process to increase survival in the organism. One possible cause for the decrease in delta opioid receptor expression following seven days of hypoxic exposure may be receptor down-regulation caused by an increased release of endogenous substances acting at delta receptors. As delta opioid receptor agonists appear promising for therapeutic potential in management of hypoxic injury, changes in delta receptor expression in response to long-term hypoxia could impact potential utilization of delta agonists in patients suffering chronic hypoxia.

Classical conditioning in the fetal rat: reinforcing properties of dynorphin A (1-13).

This study examined the reinforcing properties of dynorphin A (1-13) in a single-trial classical conditioning paradigm in the E20 rat fetus. Injection of dynorphin into the cisterna magna increased fetal motor activity and reduced facial wiping in a test of perioral cutaneous responsiveness. Dynorphin was effective as an unconditioned stimulus (US) in a classical conditioning paradigm using an artificial nipple conditioned stimulus (CS) and dynorphin A (1-13) US. The association between CS and US was dependent on activity in the kappa opioid system. Re-exposure to the artificial nipple CS after a single pairing of the nipple with dynorphin resulted in conditioned activation of the kappa opioid system. Dynorphin A (1-13) functions as a reinforcer for classical conditioning in the rat fetus after intracisternal or intrahemispheric injection, with the conditioned response depending on route of administration and site of injection.

The development of behavior before birth.

Study of the fetus in vivo provides a simple system for experimental study of early neurobehavioral development. This review summarizes research on the development of behavior before birth including studies where fetuses are exposed to stimuli that mimic features of the neonatal environment, such as milk and an artificial nipple. These stimuli reliably evoke responses from fetal subjects, including species-typical behavior such as the stretch response and oral grasping of the artificial nipple. Contingent presentations of the nipple and milk can result in classical conditioning, including activation of the endogenous opioid system. Quantitative analysis of fetal motor behavior coupled with the use of ecologically relevant sensory manipulations provide a means for assessing integrated output of the developing nervous system. A general article with the title Development of Behavior Before Birth implies a number of topics that might be discussed. One may anticipate that such an article would provide an historical overview of the field of behavioral embryology or a survey of the diverse approaches used to measure behavior in utero. Recent reviews have appeared that have adequately described historical context (Oppenheim, 1982, 1992) and research methods that currently are permitting study of prenatal behavioral development (Nijhuis, 1992; Smotherman & Robinson, 1988a), so these issues will not be addressed in the present report. Alternatively, one might expect such an article to pose speculative scenarios for prenatal learning or cognition, or to suggest how parents can interact with the fetus within the womb. The subject of prenatal enrichment has received widespread attention in the popular press, but dubious claims by authors and marketeers actually may have impeded empirical investigation of fetal behavioral capacities. Rather than belaboring issues that have been adequately addressed elsewhere, or which do not merit scientific discussion, this article will focus on the findings and implications that have emerged from experimental study of fetal behavior, primarily in nonhuman species. It is our thesis that the mammalian fetus is interesting in its own right because it exhibits a rich and sophisticated behavioral repertoire (Robinson & Smotherman, 1992a; Smotherman & Robinson, 1990), and that study of the mechanisms that regulate behavior in the nonhuman fetus can provide unique insights into the general rules that direct neurobehavioral development and the research methods needed to identify them (Robinson & Smotherman, 1988; Smotherman & Robinson, 1988b, 1994a).

Electrophysiological study on spinal antinociceptive interactions between adenosine and morphine in the dorsal horn of the rat

The effects of intrathecal 6N 6-cyclopentyladenosine (N 6-CPA), an A 1-receptor agonist, and morphine, a mu opioid-receptor agonist were studied on the electrically evoked responses of deep dorsal horn neurones in the rat. Both caused inhibitions, when applied alone, of the C-fibre evoked response and post-discharges. Enhanced inhibitory effects were observed when N 6-CPA (5 μg) was given with morphine (1 μg). Increasing the dose of morphine (5 μg) with the same dose of N 6-CPA occluded the expected inhibitions. By contrast, the Aδ-fibre evoked response, inhibited by morphine alone, was significantly facilitated by the combination. Parallel activation of purinergic and opioid inhibitory systems within the dorsal horn as well as complex interactions between them are likely.

Opioid blockade attenuates acquisition and expression of cocaine-induced place preference conditioning in rats

Endogenous opioid systems have been implicated in experimental cocaine addiction. One aspect of this involvement may be the modulation of the motivational properties of cocaine by endogenous opioids. The present study assessed the effect of opioid blockade with naloxone (NLX) on cocaine's motivational properties using the conditioned place preference procedure. Treatment with doses of NLX that did not induce place aversion (0.01-1.0 mg/kg-1, SC), dose-dependently attenuated place preference induced by cocaine (10 or 20 mg/kg-1, IP). This effect of NLX was present when administered during acquisition of cocaine-induced place preference and when administered before expression of cocaine's motivational effects. These data support the notion that the (conditioned) motivational properties of cocaine are modulated through activation of opioid systems by endogenous opioid peptides. Furthermore, it is suggested that an interaction between endogenous opioid systems and dopaminergic systems in the brain might be of importance in the motivational facilitation of experimental cocaine addiction.

Influence of naloxone on muscle sympathetic nerve activity, systemic and calf haemodynamics and ambulatory blood pressure after exercise in mild essential hypertension

To determine the effects of prior exercise and naloxone on haemodynamics, muscle sympathetic nerve activity, pituitary hormones and ambulatory blood pressure. We studied 14 mild hypertensive and 14 normotensive subjects on two days. After baseline measurements, subjects were randomly allocated to vehicle or naloxone (0.4 mg/kg) 30 min before 45 min treadmill exercise. In both groups blood pressure, stroke volume, and calf and total peripheral resistances were lower 1 h after exercise, whereas sympathetic activity was unchanged. In normotensive subjects naloxone abolished this calf vasodilation without altering muscle sympathetic nerve activity, and attenuated these haemodynamic aftereffects of exercise, implying a peripheral opioidergic mechanism. Naloxone had no haemodynamic effect in hypertensive subjects. In normotensives there was an inverse relationship between changes in blood pressure and sympathetic activity after vehicle and exercise. This was transformed by naloxone into a positive relationship (r = 0.69, P < 0.02) similar to that observed in hypertensives after vehicle and exercise. Naloxone did not alter the latter positive relationship. Naloxone altered exercise-induced changes in prolactin and luteinizing hormone, but only in normotensive males. In both groups ambulatory blood pressures and heart rates over 2 h after subjects left the laboratory were higher than the values recorded at baseline or 1 h after exercise, and were unaffected by naloxone. The depressor effect of exercise is due to peripheral vasodilation, occurs in the absence of sympathetic withdrawal and is short-lived. Endogenous opioids, activated by running, participate in the haemodynamic, sympathoneural and pituitary hormone aftereffects of exercise in normotensive subjects, whereas in hypertensives these aftereffects of exercise are achieved through non-opioidergic mechanisms. These observations are consistent with the concept that activation of endogenous opioid systems by exercise is impaired in mild hypertension.

Activation and inhibition of the endogenous opioid system in human heart failure.

In a canine model of congestive heart failure beta endorphin concentrations were high and opioid receptor antagonists exerted beneficial haemodynamic effects. In humans previous studies have suggested that opioid peptides may modify the perception of breathlessness and fatigue in heart failure. Plasma concentrations of beta endorphin were measured in patients with acute and chronic heart failure and cardiogenic shock. A subgroup of eight patients with New York Heart Association (NYHA) class III-IV heart failure was assessed for acute haemodynamic effects of naloxone, an opioid receptor antagonist. A separate group of 10 patients with class II-III heart failure, was randomised to a double blind placebo controlled study of the effects of intravenous naloxone on cardiopulmonary exercise performance. Plasma concentrations of beta endorphin were usually normal in patients with chronic heart failure and did not correlate with severity as assessed by NYHA class. In 29% of patients with acute heart failure and 71% of those with cardiogenic shock beta endorphin concentrations were high. The median concentration in the cardiogenic shock group was significantly higher than in either of the two heart failure groups and there was some evidence of a relation between beta endorphin concentrations and survival. At the doses tested, naloxone was unable to modify systemic haemodynamics, exercise performance, or symptoms in patients with chronic congestive heart failure. Circulating concentrations of beta endorphin are usually normal in patients with chronic congestive heart failure. Inhibition of the endogenous opioid system is unlikely to have therapeutic potential in heart failure.

Proenkephalin and prodynorphin mRNA level in brain of rats with absence epilepsy

An in situ hybridization method was used to estimate the proenkephalin (PENK) and prodynorphin (PDYN) mRNA levels in the brain of epileptic 6-month-old WAG Rij rats in comparison with non-epileptic: 3-month-old WAG Rij rats, 3-month-old ACl rats and 6-month-old ACl rats. The epileptic rats had a significantly higher level of PENK mRNA in the striatum as compared to non-epileptic controls. The PDYN mRNA level was significantly elevated only in the hippocampus of epileptic rats, whereas age- or strain-related changes in the striatal and cortical PDYN mRNA levels were found in both epileptic and non-epileptic rats. The changes in the biosynthetic activity of endogenous opioid peptide systems may be important for the occurrence of epileptic discharges in these animals.

Antinociception induced by exogenous and endogenous opioids: Role of different brain structures

RB 101, the mixed inhibitor of the enkephalin degrading enzymes able to cross the blood brain barrier induced similar antinociceptive effects to exogenous opiates, but produced less tolerance and dependence after chronic treatment (1). In this study we have investigated the participation of several brain structures in antinociception induced after exogenous opioid injection or activation of the endogenous opioid system with RB 101. Rats were implanted with cannulae into thalamus ventro-basal (THB), central amygdala (AMG), periaqueductal gray matter (PAG) and raphe magnus nucleus (NRM). The antinociceptive responses induced by systemic injection of morphine or RB 101 were evaluated in the tail electrical-stimulation test after local administration of the opioid antagonist methylnaloxonium (MN) into the implanted structures. The blockade of morphine and RB 101 antinociception was similar after MN administration in the THB, PAG and NRM. However, morphine responses were more efficiently blocked than the responses induced by RB101 when MN was injected into the AMG. This result suggests a different implication of AMG in endogenous and exogenous opioids induced antinociception.

Opioid involvement in alcohol drinking.

A large body of evidence indicates that the endogenous opioid system plays an important role in maintaining alcohol drinking behavior. Evidence is reviewed that indicates that the reinforcing properties of alcohol that lead to continued and repeated bouts of drinking may be due, in part, to alcohol-induced activation of the endogenous opioid system. Much of this evidence is pharmacologic in nature. Blocking the action of endogenous opioid peptides via administration of opioid antagonists significantly attenuates alcohol consumption in animals under a variety of experimental conditions. In clinical trials, opioid receptor antagonists decrease alcohol consumption, relapse rates, subjective high, and alcohol craving in outpatient alcoholics. The potential clinical utility of opioid receptor antagonists in the treatment of alcoholism and alcohol dependence is discussed.

Milk as the proximal mechanism for behavioral change in the newborn

Early experience in the context of suckling at the nipple is a crucial determinant of neurobehavioral development in mammals. In particular, milk has been recognized by developmental psychobiologists as an ecologically relevant sensory stimulus and should be viewed by clinicians as more than a source of nutrition in early human development. Gaining access to and processing milk during suckling serves as a primary focus of activity in the newborn. Because the rat fetus lacks prior exposure to milk or other suckling stimuli, it provides an excellent model system for investigating the development of milk-related responses. Fetal exposure to milk results in a cascade of behavioral, physiological and neurochemical consequences. Milk-induced activation of the endogenous opioid system plays an important role in reorganizing fetal motor activity, altering sensory responsiveness and supporting associative learning in the fetus. Subtle changes in contextual stimulation alter the ability of milk to engage different neurochemical systems. These findings suggest that the infant's first experiences with milk and other suckling stimuli may have lasting consequences for neurobehavioral development.

Does a relationship exist between the quality of stress and the motivation to ingest alcohol?

Previous experimental findings on the relationship between emotional stress and motivation to ingest alcohol are contradictory. To obtain information about this relationship we tested the effects on alcohol consumption in rats subjected to two types of chronic unavoidable stressors, intermittent immobilization and social isolation, which differ in their influence on the functional state of the endogenous opioid system. To characterize the nature and magnitude of the stress induced by these stressors, we measured their effects on functional parameters which have a close relationship to the regulatory influence of endogenous opioid peptides (endogenous opioid dependence, pain sensitivity, blood pressure). Our investigations have shown that chronic intermittent immobilization, which induced development of endogenous opioid dependence, presumably due to activation of endogenous opioid systems, did not produce increased alcohol consumption. On the contrary, chronic social isolation, which did not induce development of endogenous opioid dependence, was followed by a significant increase in alcohol consumption. It is concluded that not all types of stress produce increased alcohol consumption, but that the effect on the endogenous opioid system may be a decisive factor in determining whether a stressor produces increased alcohol consumption.

Opioids and stereotypies in coping with chronic stress

Long-term tethered housing of pigs, which is not unusual in modern pig breeding farms, largely impairs the animals in their movements and thus represents a condition of chronic restraint stress. Some tethered pigs display stereotypies, that can be blocked by the opiate receptor antagonist naloxone, suggesnng increased activity of endogenous opioid systems in these animals. We have used the tethered pig as a model to further investigate the role of opioids in changes in hormonal and physiological regulation induced by chronic stress

Antinociceptive effects of counterirritants

Counterirritants such as l-menthol, methyl salicylate, camphor, thymol and capsaicin are widely used in the treatment of mild pains and itches by topical application. However, little experimental research on counterirritants has been reported. In the present study, we investigated the antinociceptive effects and mechanisms of topically applied counterirritants, especially those of l-menthol. From the formalin test in mice, l-menthol (at a concentration of 1-30% in ethanol) showed a major effect in the early phase of pain response (0-5 min). In contrast, the antinociceptive effects of indomethacin (10 mg/kg, p.o.) were found only in the late phase of pain response (15-25 min). Furthermore, morphine (0.75-6 mg/kg, s.c.) dose-dependently inhibited both phases. l-Menthol-induced analgesia during the early phase was significantly blocked by naloxone and potentiated by bestatin. The antinociceptive effects of l-menthol were furthermore examined in dexamethasone-treated mice. l-Menthol also produced antinociceptive effects in the hot plate test of mice and hind paw pressure test of rats. l-Menthol showed mild surface and infiltrating anesthetic effects in guinea pigs. l-Menthol did not inhibit both carrageenin-induced paw edema of rats and the synthesis of prostaglandin E2 in vitro. Based on these findings, we proposed that l-menthol produces antinociceptive effects by activation of the endogenous opioid system and/or partially by local anesthetic actions without anti-inflammatory effects.

The inhibition of liver ornithine decarboxylase expression in neonatal rats by maternal separation or CNS β-endorphin is independent of the pituitary

Previously we have shown, in rat pups, that either short-term maternal separation (MS) or central (but not peripheral) administration of β-endorphin (BE) markedly decrease basal levels of ornithine decarboxylase (ODC) activity throughout the body and suppresses liver ODC reponsiveness to injected growth hormone (GH). In this study, hypophysectomized (hypox) pups were used to determine whether the pituitary mediates these effects. Hypophysectomy clearly did not prevent the inhibitory actions of MS or intracisternal (i.c.) BE on liver ODC gene expression. The inability of GH to stimulate ODC activity in hypox animals exposed to MS or given BE i.c. is not due to nutritional deprivation, as glucose supplementation did not reverse the response. The results from these studies demonstrate that the pituitary is not the conduit by which either MS or centrally-administered BE regulates liver ODC activity. Also, they support the hypothesis that BE or an analogous opioid neuropeptide is a prime organizer within the CNS of the adaptive physiological response of neonatal rats to short-term MS. As we have previously shown that autonomic neuronal pathways are not involved in the effects of MS on peripheral tissues, the data obtained suggest that increased activity of this CNS opioid system during MS triggers the release of “neurochemicals” into the bloodstream capable of suppressing growth in the mammalian neonate.

Endogenous opioid system activity following temporary focal cerebral ischemia.

We studied changes in opioid receptors (mu, delta, kappa) concentrations during temporary middle cerebral artery occlusion (MCAO) in cats by sequential displacement of unselective opioid antagonist, [3H]-diprenorphine with highly selective ligands for mu, delta and kappa, subsites. Following threshold cerebral ischemia (rCBF < 10 ml/100 g/min) there was a 2 to 3 fold increase in the 3 opioid receptor subtype concentrations at 10 min following the release of MCAO. Further, 56% of the cats depicted early postischemic hyperemia BBB opening, at 1 h and 3 h following the release of occlusion, with significant subsequent progression of brain edema. We believe that the enhanced brain opioid activity may be relevant to the neuronal damage caused by the early postischemic BBB opening.