Up-regulation of opiate receptors following chronic naltrexone treatment in mature and aged male and female rats.
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Aging↗
Biomedical subjects
M T Bardo
Publications and source records attributed to M T Bardo.
Chronic treatment with naltrexone enhances morphine-stimulated dopamine neurotransmission: neurochemical and behavioral evidence.
Rats were implanted for 10 days with a slow-release pellet of naltrexone or were given sham surgery. At one of various different intervals during or after implantation of the pellet, the synthesis of dopamine (DA) was assessed in the nigrostriatal and mesolimbic systems. The results indicated that naltrexone alone was without effect on the synthesis of DA. However, one day after removal of the pellet, naltrexone-treated animals displayed an enhanced response to the DA-stimulatory action of morphine (15 mg/kg) in both the nigrostriatal and mesolimbic systems. This change was accompanied by an increase in specific binding of the mu-specific radioligand [3H]DAGO in whole brain and by an increase in the depressant action of morphine on locomotor activity. In contrast, at 10 days after removal of the pellet, naltrexone was without effect on morphine-induced changes in the synthesis of DA and locomotor activity, thus indicating that the supersensitivity to morphine was transient. These results support the idea that opioids modulate DAergic neurotransmission in the nigrostriatal and mesolimbic pathways and that this modulatory role may underlie opiate-induced changes in locomotor behavior.
Animals↗
Expression of morphine-conditioned hyperactivity is attenuated by naloxone and pimozide.
The present experiments assessed whether morphine-conditioned hyperactivity could be attenuated by either the opiate antagonist naloxone or the dopamine antagonist pimozide. Both of these antagonists were shown to block the unconditioned hyperactivity induced by 2 mg/kg morphine (Experiment 1). Rats were then conditioned by pairing this dose of morphine repeatedly with a distinctive environment (Experiment 2). Following several drug-environment pairings, rats displayed a hyperactive conditioned response (CR) when exposed to the environment in the absence of the drug. CR expression was counteracted by 1 mg/kg naloxone and was attenuated by pimozide (0.25, 0.33, and 0.4 mg/kg) in a dose-related manner. These findings suggest that the unconditioned and conditioned hyperactive responses produced by morphine may involve similar neuropharmacologic substrates.
Animals↗
Chronic naltrexone supersensitizes the reinforcing and locomotor-activating effects of morphine.
Rats were implanted for 10 days with a slow-release naltrexone pellet and then the pellet was removed. Sham-control animals were treated similarly, except no pellet was implanted. One day after pellet removal or sham treatment, animals were assessed for morphine-induced conditioned place preference (CPP) or locomotor activity. CPP was evident in sham animals following two conditioning trials using 5 mg/kg subcutaneous morphine (Experiment 1) and following one conditioning trial using 8 mg/kg intravenous morphine (Experiment 2). Animals conditioned while implanted with a naltrexone pellet showed no morphine-induced CPP. More important, one day after pellet removal, naltrexone-pretreated animals given one conditioning trial with 5 mg/kg intravenous morphine displayed a greater preference for morphine-associated cues relative to sham animals given morphine (Experiment 3 and 4). This single IV morphine dose was insufficient to produce CPP in sham animals, suggesting that naltrexone-induced supersensitization may only be evident at a morphine dose below the reinforcing threshold in control animals. Further, chronic naltrexone potentiated the locomotor-activating effect of 2 mg/kg subcutaneous morphine but not of either 1 or 5 mg/kg morphine (Experiment 5). Behavioral supersensitization assessed by morphine-induced locomotor activation was transient, as it was evident one day, but not either three or 10 days following pellet removal (Experiment 6). These results confirm the functional significance of opiate receptor up-regulation following chronic opioid blockade.
Animals↗
Repeated testing attenuates conditioned place preference with cocaine.
Cocaine-treated rats acquired a preference for cocaine-associated contextual stimuli (CS) relative to saline-injected control rats. However, when animals were given repeated tests for conditioned place preference intermittent between conditioning trials, they displayed an attenuation in strength of conditioning. This attenuation was not due to pharmacologic tolerance (Experiment 1), but rather reflected a disruption in learning due to exposure to the CS alone (Experiment 2). Like other examples of classical conditioning, the strength of the conditioned response (CR) as assessed by the conditioned place preference model may be influenced by partial reinforcement.
Animals↗
Single-trial conditioned place preference using intravenous morphine.
Experiments were performed to investigate single-trial conditioned place preference (CPP) using intravenous morphine in rats. Single-trial CPP was obtained when morphine (8 mg/kg) was paired for either 15 or 30 min with a distinct white compartment. When morphine administration was delayed for either 15 or 25 min after the beginning of a 30-min exposure to the white compartment, single-trial CPP was not obtained. Intravenous naloxone (2 mg/kg) also blocked single-trial CPP when administered 15 min after the beginning of the 30-min exposure to the white compartment with morphine, but naloxone by itself did not alter place preference. The results from these experiments indicate that single-trial CPP using intravenous morphine may offer a useful animal model to assess the reinforcing efficacy of the initial drug experience.
Animals↗
Effects of morphine on sprouting of locus coeruleus fibers in the neonatal rat.
Acutely (by 48 h), as well as after one month survival, morphine (20 mg/kg) significantly potentiated the extent of noradrenergic degeneration in the forebrain of newborn rats caused by 50 mg/kg of 6-hydroxydopamine (6-OHDA) s.c. This was associated with increased regenerative sprouting in the cerebellum and pons-medulla as determined by measurements of norepinephrine (NE) concentration and [3H]NE uptake. This potentiating effect of morphine was not seen in either forebrain, brainstem, or cerebellum if it was administered to newborn rats with a 24-h delay following 6-OHDA. Clonidine (0.1 mg/kg) which, like morphine, decreases locus coeruleus activity, acutely tended to enhance the acute degenerative effects of 6-OHDA, whereas yohimbine (5 mg/kg), an alpha 2-antagonist which increases locus coeruleus activity, significantly attenuated the acute effect of 6-OHDA in the forebrain. In order to determine whether morphine directly alters the regenerative growth of neurons independently of its acute interaction with 6-OHDA, we explored its effect on the collateral sprouting of locus coeruleus projections induced by midcollicular hemisection. Unilateral midcollicular hemisection in neonates resulted, at 2 months of age, in a 91% reduction of NE concentration in the ipsilateral forebrain and an increase in the ipsilateral cerebellar hemisphere to over 200% of control. Significant increases of a slightly smaller magnitude were found in the cerebellar vermis, pons-medulla and the colliculi. Morphine given simultaneously with the lesion significantly attenuated this collateral sprouting in the cerebellar hemisphere and colliculi. These results indicate that morphine potentiates the initial toxicity of 6-OHDA, perhaps by altering activity of locus coeruleus neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic Fibers↗
Conditioned place preference with morphine: the effect of extinction training on the reinforcing CR.
Rats were injected with either morphine (5 mg/kg) or saline in association with one set of distinct environmental stimuli, and injected with saline in association with a different set of stimuli. After four conditioning trials, animals were given a 15-minute free-choice test to determine which stimulus environment was preferred. Animals displayed CPP as a significant increase in duration spent within the morphine-associated environment, but did not display any change in number of entries into that environment. In contrast, when extinction training was given following CPP, animals displayed a significant decrease in duration spent per entry into the morphine-associated environment, but did not display any change in total duration spent in that environment. These results suggest that assessment of the reinforcing conditioned response (CR) in the CPP model may require measurement of both duration spent in and number of entries into the drug-associated environment.
Animals↗
Opiate receptor supersensitivity produced by chronic naloxone treatment: dissociation of morphine-induced antinociception and conditioned taste aversion.
In three separate experiments, rats were used to assess the effects of chronic administration of naloxone on specific binding of 3H-naloxone in various regions of the central nervous system (CNS) and on the efficacy of morphine to produce antinociception and a conditioned taste aversion. Chronic naloxone treatment increased opiate binding in medulla-pons, midbrain, hypothalamus, hippocampus, striatum, and prefrontal cortex, but not in either spinal cord or cerebellum. In those CNS regions exhibiting increased opiate binding, the duration of increased binding following termination of the naloxone treatment differed between regions. In conjunction with the increase in opiate binding, the efficacy of morphine to produce antinociception was potentiated, while the efficacy to produce a conditioned taste aversion was unchanged. Moreover, the administration of naloxone during behavioral testing blocked completely the antinociceptive effect, but not the aversive effect, of morphine. These results indicate that morphine-induced antinociception and conditioned taste aversion may be dissociated neuropharmacologically.
Animals↗
Chronic naltrexone increases opiate binding in brain and produces supersensitivity to morphine in the locus coeruleus of the rat.
Rats were implanted subcutaneously for 2-4 weeks with slow-release pellets of naltrexone (10 mg) or placebo and then the pellets were removed. One day after removal of the pellet, animals were either (1) sacrificed and various CNS regions examined for specific binding of [3H]naloxone, [3H]etorphine or [3H]rauwolscine or (2) they were anesthetized and prepared acutely for assessing morphine-induced changes in the spontaneous activity of neurons in the locus coeruleus (LC). Naltrexone treatment significantly increased the number of specific binding sites for opiates, but not for alpha 2-adrenergic antagonists, in spinal cord, hypothalamus, striatum and cortex. Specific binding of [3H]naloxone was also increased in the LC. The spontaneous activity of neurons in the LC was reduced by the chronic naltrexone treatment, suggesting that these neurons became supersensitive to the tonic inhibitory effect of endogenous opioid peptides. Moreover, neurons in the LC of chronic naltrexone-treated rats exhibited an enhanced response to the inhibitory effects of morphine administered systemically. These results demonstrate that chronic opiate receptor blockade increases the number of receptor sites for morphine and that this increase in receptors is accompanied by a neuronal supersensitivity in the LC to morphine which can be assessed electrophysiologically.
Animals↗
Age-related differences in the effect of chronic administration of naloxone on opiate binding in rat brain.
Infant and adult rats were injected chronically with either naloxone or saline for 21 consecutive days. At various intervals after cessation of the pretreatment with naloxone, animals were sacrificed and assessed for specific binding of [3H]naloxone in different regions of the CNS. Infants displayed an increase in opiate binding in the spinal cord, hypothalamus, striatum and cortex one day after cessation of the pretreatment with naloxone, but the increase in opiate binding was dissipated within one week after cessation of the pretreatment. The increase in opiate binding in infants was accompanied by an increase in the antinociceptive efficacy of morphine. In contrast to infants, adults failed to display any alteration in opiate binding following the chronic pretreatment with naloxone. Infants may be especially susceptible to naloxone-induced receptor supersensitivity because infants excrete naloxone more slowly than adults, and thus their opiate receptors may be blocked for a longer duration following an injection of naloxone.
Age Factors↗
Norepinephrine depletion in the spinal cord gray matter of rats with experimental allergic encephalomyelitis.
Norepinephrine and dopamine concentrations were determined by radioenzymatic assay in discrete gray matter regions of the spinal cords of rats with experimental allergic encephalomyelitis (EAE). Norepinephrine was depleted in most spinal cord regions of EAE rats compared with controls, whereas dopamine depletion in EAE rats was restricted to the cervical dorsal horn. There was a rostrocaudal gradient of norepinephrine reduction in the spinal cords of the EAE rats with most severe depletion in the lumbar region. The results of this experiment confirmed recent anatomical observations that suggested that catecholamine-fluorescent axons and terminals were damaged in spinal cords of rats with EAE.
Animals↗
Differential effects of chronic morphine and naloxone on opiate receptors, monoamines, and morphine-induced behaviors in preweanling rats.
Rats were administered either chronic morphine, naloxone or saline from 1 to 21 days of age. At 22 days of age, animals were sacrificed and various CNS areas were assayed for specific binding of [3H]naloxone and steady-state levels of norepinephrine, dopamine and serotonin, as well as turnover of norepinephrine and dopamine. In addition, some animals at 22 days of age were assessed for morphine-induced changes in activity, hot-plate paw-lick latency, and rectal body temperature. Chronic naloxone treatment produced an increase in the number of ligand binding sites in hypothalamus, striatum and cortex, but did not alter monoamine systems or the efficacy of morphine. In contrast, chronic morphine treatment produced tolerance to the hypoactive and antinociceptive effects of morphine, but did not alter ligand binding or monoamine systems. These results demonstrate that developing opiate receptor systems in brain are more responsive to chronic receptor blockade than to chronic receptor activation and that an alteration in the development of opiate receptor systems does not necessarily produce a concomitant alteration in either monoamine systems or the behavioral efficacy of morphine.
Animal Population Groups↗
Opiate receptor development in midbrain and forebrain of posthatch chicks.
Specific binding [3H]naloxone to midbrain and forebrain was examined from chicks which were either 1, 7, 14, 21 or 28 posthatch days of age. While there was a significant age-related increase in the total number of [3H]naloxone binding sites in both brain regions, the increase was greater in magnitude in forebrain than in midbrain. In both brain regions, there was a concomitant age-related decrease in the density of receptor sites without any alteration in receptor affinity for naloxone. The decrease in receptor density was more rapid in onset and was greater in magnitude in midbrain than in forebrain.
Aging↗
An improved filtration procedure for measuring opiate receptors in small regions of rat brain.
A modified filtration method for in vitro receptor binding was used to determine specific binding of [3H]naloxone to small regions of adult rat brain. Reliable determinations of ligand binding were quantified with about 50 micrograms of protein per assay tube. Large differences in [3H]naloxone binding were obtained between various brain nuclei, and these differences were consistent with prior determinations of opiate receptor densities in various rat brain nuclei using autoradiographic techniques.
Animals↗
Within- and between-subjects differences in the effect of morphine in mice.
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Analgesia↗
Single-dose tolerance to morphine-induced analgesic and hypoactive effects in infant rats.
A single injection of morphine or isotonic saline was administered to rats at either 1, 5, 9, ro 13 days of age. At 26-29 days of age, animals were tested for pain responsivity and activity following either morphine (5 mg/kg) or saline. Animals which received morphine at 1 day of age displayed tolerance at 26 days of age, whereas animals which received morphine at either 5, 9, or 13 days of age failed to display tolerance. This age-dependent change in susceptibility to single-dose morphine tolerance may involve alterations in opiate receptor ontogeny.
Age Factors↗
The role of hot plate and general environmental stimuli in morphine analgesic tolerance.
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Analgesics, Opioid↗