Biomedical subjects

S G Holtzman

Publications and source records attributed to S G Holtzman.

At least 73 records · Page 4Linked to original sources

PubMed1993

Delta-opioid receptor antagonists attenuate motor activity induced by amphetamine but not cocaine.

Naloxone and naltrindole attenuate the locomotor response to amphetamine, implicating delta-opioid receptors in the opioid-antagonist/amphetamine interaction. To determine the role of delta-opioid receptor subtypes in this phenomenon, rats were pretreated with the following selective antagonists administered intracisternally: naltrindole, [D-Ala2,Leu5,Cys6]enkephalin (DALCE, delta 1 receptor selective), naltrindole-5'-isothiocyanate (delta 2 receptor selective). Cumulative dose-response curves to amphetamine were constructed (saline, 0.1, 0.4, 1.6 and 6.4 mg/kg s.c.), with injections every 30 min. Naltrindole was also tested against cumulative doses of cocaine (saline, 3.0, 10, 30 and 56 mg/kg i.p.). Gross and fine motor activity were recorded for 20 min, commencing 10 min postinjection. Amphetamine and cocaine dose dependently increased both gross and fine movements. Naltrindole (10 micrograms) attenuated the gross but not fine activity response to amphetamine, but 10 or 30 micrograms failed to influence the response to cocaine. Naltrindole-5'-isothiocyanate (30 micrograms) attenuated slightly but significantly the gross activity response to amphetamine, whereas DALCE (30 micrograms) was without effect. However, a combination of 10 micrograms each of DALCE and naltrindole-5'-isothiocyanate markedly attenuated the amphetamine-induced increases in gross movements without altering fine activity. These data provide further evidence for the involvement of delta-opioid receptors in the modulation of behavioral effects of amphetamine; both delta 1- and delta 2-opioid receptors appear to play a role. The differential effects of opioid antagonists on locomotor activity stimulated by amphetamine and cocaine suggests differences in the mechanism of action of these drugs not previously appreciated.

Amphetamine↗

PubMed1993

Restraint stress potentiates analgesia induced by 5'-N-ethylcarboxamidoadenosine: comparison with morphine.

mu-Opioid receptor agonists, e.g. morphine, produce analgesia that can be potentiated by restraint stress. Adenosine receptor agonists, e.g. 5'-N-ethylcarboxamidoadenosine (NECA), also produce analgesia. To determine if adenosine-induced analgesia is also potentiated by stress, dose- and time-effect curves for NECA (0.01-0.1 mg/kg s.c.) were generated in adult male Sprague-Dawley rats either unrestrained or restrained in Plexiglas cylinders, using the tail-flick assay. Morphine (1.0-5.6 mg/kg s.c.) was also tested for comparison. Both compounds produced dose-dependent increases in tail-flick latencies. This effect of both drugs was potentiated in restrained rats. The opioid receptor antagonist, naltrexone (1.0 mg/kg s.c.) blocked completely the effect of morphine in both groups and attenuated the stress-induced potentiation of NECA-induced analgesia. The adenosine receptor antagonist, caffeine (10.0 mg/kg s.c.), blocked the analgesic effect of NECA but not that of morphine. These results indicate that adenosine-mediated analgesia is potentiated by restraint stress and suggest a role for endogenous opioids in the mediation of stress-induced potentiation of analgesia.

Adenosine↗

PubMed1993

The potentiating effects of restraint stress and continuous naloxone infusion on the analgesic potency or morphine are additive.

The analgesic potency of morphine in the rat can be increased by either continuous administration of an opiate antagonist, which also increases the number of mu-opioid receptors in the brain, or by immobilization stress. To examine further the plasticity of brain opioid mechanisms, this study assessed the combined effects of continuous naloxone treatment and physical restraint on the analgesic potency of morphine. Osmotic pumps releasing 0.3 mg/kg/h of naloxone were implanted subcutaneous (SC) in two groups of rats for 7 days and empty (SHAM) pumps were implanted in two other groups. Twenty-four hours after the pumps were removed, all animals were injected with morphine in cumulative doses and tested in the tail-flick procedure. One group of naloxone-treated rats and one group of SHAM-treated rats were tested while restrained; the other two groups were tested while unrestrained. Naloxone infusion alone and restraint alone each increased significantly the analgesic potency of morphine by 1.4-fold whereas the combination of these two treatments increased analgesic potency by almost 2-fold, significantly more than either treatment alone. All animals were retested with morphine 6 days later; the analgesic potency of morphine in the SHAM groups was still potentiated by stress but the potentiating effect of the earlier naloxone infusion was no longer evident. It appears that the opioid receptors mediating stress-induced potentiation of morphine-induced analgesia can be upregulated transiently by 7-day infusion of naloxone.

Animals↗

PubMed1993

Naltrexone in vivo protects mu receptors from inactivation by beta-funaltrexamine, but not kappa receptors from inactivation by nor-binaltorphimine.

The ability of the competitive opioid antagonist, naltrexone, to protect opioid receptors from inactivation by the nonequilibrium antagonists, beta-funaltrexamine (beta-FNA) and nor-binaltorphimine (nor-BNI), was examined in vivo. Male rats were injected SC with 10 mg/kg naltrexone or saline, 30 min before being injected intracisternally (IC) with water, 10 micrograms beta-FNA, or 1.0 or 10 micrograms nor-BNI. The rats were tested for analgesic responses to either U69,593 (nor-BNI groups) or morphine (beta-FNA groups), on a 50 degrees C hot plate, 24 h later. Morphine produced dose-related increases in the latency to paw lick in rats that received water (IC) (mean ED50 = 3.2 mg/kg). Little or no analgesia occurred after 1.0-30 mg/kg of morphine in animals that had received saline (SC) and 10 micrograms beta-FNA (IC) 24 h earlier. Pretreatment with 10 mg/kg naltrexone attenuated the antagonist effects of beta-FNA (morphine ED50 = 10.8 mg/kg). U69,593 also produced analgesia in animals that received water (IC) (ED50 = 0.97 mg/kg). This analgesia was dose-dependently blocked by nor-BNI for up to 7 days. Naltrexone did not inhibit the actions of nor-BNI. Thus, naltrexone prevented inactivation of mu receptors by beta-FNA but not inactivation of kappa receptors by nor-BNI, suggesting that antagonist interactions with mu receptors are different from those with kappa receptors.

Analgesics↗

PubMed1993

Discriminative stimulus effects of the PCP/sigma-ligand (+)-N-allylnormetazocine in monkeys.

(+)-N-Allylnormetazocine [(+)-NANM] binds to both the phencyclidine (PCP) receptor and the sigma-site in brain, with some selectivity for the latter. In rats, the discriminative stimulus effects of (+)-NANM are primarily PCP like. The present study was performed to determine if the discriminative effects of (+)-NANM in a primate species might reflect the actions of this drug at the sigma-site. Six squirrel monkeys were trained to discriminate between IM injections of saline and 1.0 mg/kg (+)-NANM in a two-choice discrete-trial avoidance procedure. In tests of stimulus generalization, dose-dependent increases in trials completed on the (+)-NANM choice lever were produced by (+)- and (-)-NANM, by PCP and the PCP-like drugs MK-801 and thienylcyclohexyl-piperidine, and by the opioids (+)- and (-)-cyclazocine and dextrorphan; order of potency correlated with reported affinities for the PCP receptor. High-affinity sigma-ligands, (+)-pentazocine, 1,3-di-ortho-tolylguanidine (DTG), haloperidol, and BMY 14802, as well as agonists at mu- and kappa-opioid receptors, occasioned selection of the saline-appropriate choice lever. Selection of the (+)-NANM choice lever was reduced by up to 35-50% when 1.0 mg/kg (+)-NANM was given concurrently with haloperidol or BMY 14802, but was not affected substantially by (-)-butaclamol, another sigma-ligand, or by naltrexone, an opioid antagonist. The discriminative effects of (+)-NANM in squirrel monkeys appear to be mediated largely by the PCP receptor and not by the sigma-site or opioid receptors.

Animals↗

PubMed1992

Effects of naloxone infusion upon spontaneous and amphetamine-induced activity.

Naloxone-filled (1.0 mg/kg per h) or sham pumps were implanted subcutaneously (s.c.) in rats on day 0 and removed on day 7. Spontaneous locomotor activity was lower in naloxone-infused rats on day 3 only. Cumulative dose-response curves to D-amphetamine were constructed in separate groups on day 6 or day 8 (0.0-6.4 mg/kg s.c.). On day 6, naloxone infusion attenuated the gross movement response to D-amphetamine, but not the fine movement response. There were no differences in the response of naloxone- or sham-infused rats to D-amphetamine on day 8. Therefore, withdrawal from continuous naloxone infusion had no influence upon spontaneous or D-amphetamine-stimulated activity.

Animals↗

PubMed1992

Long term kappa-opioid receptor blockade following nor-binaltorphimine.

This study determined the influence of nor-binaltorphimine (nor-BNI, 10 micrograms intracisternally), 1, 7 and 21 days post-administration, upon spiradoline-induced antinociception measured in the hot-plate test. On each test day, nor-BNI prevented the spiradoline-induced increase in the latency of rats to paw-lick without affecting the antinociceptive response to morphine. These data suggest that a single administration of nor-BNI can cause a long term blockade of kappa-opioid receptors in rats.

Analgesics↗

PubMed1992

Apparent pA2 value of naltrexone is not changed in rats following continuous exposure to morphine or naloxone.

Chronic opioid antagonist administration increases opioid binding sites and potentiates behavioral responses to morphine. Conversely, chronic opioid agonist administration attenuates behavioral responses to morphine, though this is not necessarily accompanied by a parallel loss of binding sites. We examined the possibility that the in vivo affinity of the mu receptors might be altered as a consequence of the continuous administration of either naloxone or morphine. Rats were implanted sc with naloxone- or morphine-filled osmotic pumps; control animals were implanted with sham pumps. One week later, 24 hr after removing the osmotic pumps, cumulative dose-response curves for fentanyl analgesia were generated in the presence of 0.0, 0.03, 0.1, or 0.3 mg/kg naltrexone, using a tail-flick procedure. The analgesic ED50 (with 95% C. L.) of fentanyl in sham implanted animals, following saline pretreatment was 0.027 mg/kg (0.019, 0.039). The potency of fentanyl was decreased in rats infused with morphine, ED50 = 0.051 mg/kg (0.028, 0.093), and increased in rats that received naloxone, ED50 = 0.018 mg/kg (0.015, 0.022). The mean apparent pA2 value for naltrexone (with 95% C.L.) in the control group was 7.7 (7.5, 7.9). No differences were detected in animals that had received either naloxone or morphine for 7 days, pA2 = 7.8 (7.5, 8.1) and 7.4 (7.3, 7.6), respectively. Our results indicate that there is no change in the apparent affinity of the mu-receptor following continuous exposure to either an opioid agonist or antagonist, at a time when the analgesic potency of the agonist is decreased or increased, respectively.

Analysis of Variance↗

PubMed1992

Naloxone reduces amphetamine-induced stimulation of locomotor activity and in vivo dopamine release in the striatum and nucleus accumbens.

This study tested the possibility that naloxone (NX), an opioid antagonist, reduces the behavioral effects of amphetamine (AMPH) in rats by attenuating the dopaminergic response to AMPH. In the first experiment, adult, male rats were injected SC with either NX (5.0 mg/kg) or saline and 30 min later received doses of AMPH (0.0, 0.1, 0.4, 1.6, and 6.4 mg/kg) cumulatively at 30-min intervals. Gross locomotor counts following AMPH administration were significantly lower for rats pretreated with NX than for rats pretreated with saline. In the second experiment, the same drug treatments were given while performing microdialysis in either the striatum (STR) or nucleus accumbens (NACC). STR rats treated with vehicle showed a larger percentage increase in DA levels following AMPH treatment than did NACC rats treated with vehicle. NX pretreatment did not affect dopamine concentrations in either brain region. However, compared to pretreatment with saline pretreatment with NX significantly decreased the dopaminergic response to AMPH in the STR. There was no difference between the two groups in the peak dopaminergic response to AMPH in the NACC, but there was a significant AMPH x treatment x time interaction due to differences between the groups during the later portion of the response to 6.4 mg/kg AMPH. There was also a difference in locomotor activity following AMPH treatment between NX- and saline-treated subjects during dialysis. These findings suggest that a decrease in the dopaminergic response to AMPH is the mechanism by which NX attenuates behavioral stimulant effects of AMPH. In addition, there is a difference between the STR and NACC in dopaminergic responsiveness to AMPH.

Animals↗

PubMed1992

Potentiation of morphine analgesia in rats given a single exposure to restraint stress immobilization.

Rats exposed to restraint stress and injected with morphine show significantly greater increases in tail-flick latency compared to unstressed rats. However, it is not necessary for rats to be restrained at the time of testing to elicit a potentiated analgesic response to morphine. We reported recently that analgesia induced by 4.0 mg/kg morphine was significantly potentiated in rats that had been restrained for only 1 h at 24 h prior to testing. One purpose of the present study was to extend this observation by determining the ability of a single exposure to restraint stress to potentiate dose-dependently morphine (0.0, 2.0, 4.0, and 8.0 mg/kg)-induced analgesia in the tail-flick test. A second purpose was to assess the generality of the phenomenon by determining whether prior restraint would potentiate the analgesic effect of morphine in another common analgesic assay, the hot-plate test. Dose- and time-course (20-120 min) curves for morphine were generated in rats exposed to one of two treatments: no restraint stress (NS) and a single exposure to 1 h of restraint (RS). Rats subjected to 1 h of restraint and tested 24 h later displayed significant time- and dose-dependent potentiation (1.3-2.0-fold) of morphine-induced analgesia compared to unstressed rats in both the tail-flick and hot-plate tests. These results demonstrate that a single period of restraint is sufficient to activate the mechanisms responsible for potentiation of morphine-induced analgesia and that the degree to which stress modified morphine's analgesia can be demonstrated using both the tail-flick and hot-plate assays.

Animals↗

PubMed1992

Intake of sweet water attenuates restraint-stress-induced potentiation of morphine analgesia in rats.

The analgesia induced in rats by morphine is potentiated by restraint-stress exposure and is reduced in rats that have been consuming a sweet solution. The purpose of the present study was to determine whether the potentiation of morphine-induced analgesia following restraint immobilization would be attenuated in rats consuming a sweet solution. Groups of rats were maintained on unsweetened water or allowed 2 h of daily access to a solution of saccharin and glucose (SG). Half of the rats in each of these groups were subjected to 1 h of restraint stress (groups RS and RS+SG) and the other half in each group were not stressed (groups NS and NS+SG). Rats then underwent 1 h of RS treatment or were nonstressed (NS). The next day all rats were injected subcutaneously with morphine (0.0, 4.0, 8.0, or 16 mg/kg) and analgesia was assessed using the tail flick assay. ED50S (mg/kg) were calculated for each treatment group; NS = 5.8, RS = 1.6, NS+SG = 6.4, and RS+SG = 4.4. Our results demonstrate that RS potentiated morphine-induced analgesia in rats given access to SG as well as non-SG exposed rats that displayed ED50S 1.5 and 3.9 times lower than their respective controls. RS-treated rats that consumed SG solution had significantly lower tail flick latencies than did non-SG exposed rats. Additionally, tail flick latencies of rats in the nonstressed and NS+SG groups did not significantly differ. We conclude that the brain mechanism(s) responsible for RS-induced potentiation of morphine antinociception are attenuated by intake of a sweet solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMed1992

Interaction between opioid antagonists and amphetamine: evidence for mediation by central delta opioid receptors.

Naloxone, the opioid receptor antagonist, attenuates the effects of amphetamine in a wide range of behavioral paradigms. To determine the role of the opioid receptor subtypes in this phenomenon, subtype-selective opioid receptor antagonists were administered intracisternally to rats either as a 15-min [naloxone methiodide (NX.M) and naltrindole (NTI)] or a 24-hr [beta-funaltrexamine (beta-FNA) and norbinaltorphimine (nBNI)] pretreatment. Cumulative dose-response curves to amphetamine were constructed (saline, 0.1, 0.4, 1.6 and 6.4 mg/kg s.c.) with dosing every 30 min. Motor activity (gross and fine movements) was recorded for 20 min, commencing 10 min postinjection. Amphetamine dose-dependently increased both fine and gross movements. NX.M (30 micrograms) and NTI (10 and 30 micrograms) attenuated the gross activity response to amphetamine but did not alter the increase in fine movements. Lower doses of NX.M (2.0 and 10 micrograms) potentiated the fine activity response to amphetamine without any effect on the gross movements. Pretreatment with beta-FNA (1.25-20 micrograms), nBNI (10 and 30 micrograms) or NX.M (5.0 mg/kg s.c.) did not influence the response to amphetamine. However, beta-FNA and nBNI blocked the antinociceptive effects of morphine and spiradoline, respectively, indicating that these antagonists were tested under appropriate conditions for opioid receptor blockade. These data indicate a central site of action for the opioid antagonist-amphetamine interaction. The ability of NX.M (i.c.) and NTI, but not beta-FNA or nBNI, to influence the motor activity response to amphetamine implicates delta receptors in the opioid-mediated modulation of the behavioral stimulant effects of amphetamine.

Amphetamine↗

PubMed1992

Development of tolerance to the analgesic activity of mu agonists after continuous infusion of morphine, meperidine or fentanyl in rats.

We investigated the role of intrinsic activity in the ability of mu-opioid agonists to produce tolerance to the analgesic effects of other mu agonists. Dose-response curves were generated for each test drug before and 24 hr after 1 week s.c. agonist infusions, using a tail-flick procedure in male rats. Morphine tolerance was dose-dependent over a range of doses, 0.3 to 1.4 mg/kg/hr, infused for 7 days by osmotic pump; 0.8 mg/kg/hr (1/4 acute ED50/hr) shifted the morphine dose-response curve roughly 2-fold to the right. Morphine, fentanyl or meperidine were then infused for 1 week to induce tolerance; doses were based on equipotent acute s.c. doses (1/4 ED50/hr). Drugs tested for analgesic activity, using a cumulative dosing procedure, included morphine, fentanyl, meperidine, methadone, buprenorphine, etorphine and levorphanol. The relative potency (RP) was calculated for each animal by dividing the preinfusion analgesic ED50 by the postinfusion ED50. The potency of morphine, fentanyl, meperidine and levorphanol decreased after a 7-day infusion of 0.8 mg/kg/hr morphine (RP = 0.44-0.70), but the potency of etorphine (RP = 0.85) and methadone (RP = 0.78) were not significantly changed. Chronic infusions of 6.25 mg/kg/hr meperidine produced more tolerance than did morphine (RP = 0.11-0.51). No significant change in analgesic potency was seen in six of the seven test drugs after infusions of 0.01 mg/kg/hr fentanyl (RP = 0.81-1.27). Buprenorphine did not produce an analgesic response in rats that received infusions of any of the three mu agonists. The RP of drugs with low intrinsic activity was lower than the RP of high efficacy drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗

PubMed1991

Do adenosinergic substrates mediate methylxanthine effects upon reinforcement thresholds for electrical brain stimulation in the rat?

Caffeine and other methylxanthines elevate reinforcement threshold for electrical brain stimulation with an order of potency suggesting that the effect is mediated by antagonism of adenosine A2 receptors. The purpose of this study was to evaluate further the possible mechanism by which caffeine and other methylxanthines elevate reinforcement thresholds for ICSS. Drugs known to affect adenosinergic transmission in predictable ways, adenosine receptor agonists and antagonists and benzodiazepine agonists and inverse agonists, were tested to determine their effect upon reinforcement threshold. Both the selective A1 adenosine agonist, R(-)-PIA, and the non-selective A1/A2 adenosine agonist NECA failed to alter reinforcement thresholds, as did CGS 15943, a potent non-xanthine non-selective adenosine receptor antagonist. Chlordiazepoxide, a benzodiazepine agonist, lowered reinforcement thresholds and FG 7142, a benzodiazepine inverse agonist, elevated reinforcement thresholds, perhaps corresponding to their anxiolytic and anxiogenic subjective effects in humans. However, another benzodiazepine agonist, midazolam and another inverse agonist, beta-CCE, did not alter reinforcement thresholds. These results fail to support a general role for adenosinergic systems in the threshold-elevating effect of methylxanthines.

Adenosine↗

PubMed1991

Naltrexone-sensitizing effects of centrally administered morphine and opioid peptides.

Rats were trained to lever-press on a multiple-trial, fixed-interval, 3-min schedule of food-reinforcement; each trial consisted of a 10-min time-out and a 9.5-min response period. Naltrexone, injected s.c. prior to each trial, reduced response rates in a dose-related fashion, with an ED50 of 21 mg/kg. Four-hour pretreatment with i.c.v. morphine (3.0-30 micrograms) produced leftward shifts of the naltrexone dose-effect curve of up to 3 orders of magnitude. The selective mu agonist, [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO; 0.1-0.3 microgram i.c.v.), sensitized animals to the rate-decreasing effects of naltrexone by more than 2 orders of magnitude. Pretreatment with the selective kappa agonist, dynorphin A-(1-17) (30 micrograms i.c.v.) or the selective delta agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE; 30-100 micrograms i.c.v.) induced moderate sensitization with leftward shifts of 1.0-1.5 log units. Thus, the naltrexone-sensitizing effect of acute opioid pretreatment is centrally mediated, consistent with the hypothesis that the phenomenon is related to the initiation of opioid physical dependence. Further, the effect appears to be mediated predominantly by mu-opioid receptors, because mu agonists consistently produced the largest sensitization to naltrexone.

Animals↗

PubMed1991

Discriminative stimulus effects of spiradoline, a kappa-opioid agonist.

This study represents the initial step in assessing the discriminative effects of spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg/kg spiradoline or 3.0 mg/kg morphine in a discrete-trial shock-avoidance/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED50S for spiradoline and U50,488 were 0.66 and 8.71 mg/kg, respectively), but selected the choice lever appropriate for saline in generalization tests with graded doses of morphine, phencyclidine, and agonist-antagonist opioids with varying degrees of kappa activity, ethylketocyclazocine, nalorphine, and butorphanol. Morphine-trained rats did not generalize to spiradoline. Naltrexone (0.01 or 0.1 mg/kg) blocked surmountably the discriminative effects of both spiradoline and morphine, but was approximately 10-fold less potent against spiradoline. These results indicate that the discriminative effects of spiradoline are mediated by kappa-opioid receptors; meaningful mu-opioid and PCP/sigma components of action were not in evidence. The potency and apparent pharmacological selectivity of spiradoline suggest the potential value of this drug for studying kappa-opioid-mediated stimulus control of behavior.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1991

CGS 15943, a nonxanthine adenosine receptor antagonist: effects on locomotor activity of nontolerant and caffeine-tolerant rats.

CGS 15943 (0.1-10 mg/kg, IP) dose-dependently increased the locomotor activity of rats to the same extent as caffeine (1.0-100 mg/kg, IP) did and was approximately 26 times more potent than caffeine. N-Ethylcarboxamidoadenosine (0.001-0.01 mg/kg, SC), an analog of adenosine, dose-dependently decreased locomotor activity; this effect was antagonized surmountably by concurrent administration of CGS 15943. The apparent pA2 value for this interaction, 6.57, was approximately 1.5 log-units (28-fold) higher than the pA2 for caffeine-NECA reported previously. Rats consuming 70 mg/kg/day of caffeine via their drinking water were tolerant to the stimulation of locomotor activity induced by both caffeine and CGS 15943. These results suggest that caffeine and CGS 15943 increase locomotor activity by a common mechanism of action possibly involving adenosine receptors or a cellular element conformationally similar to adenosine receptors.

Adenosine↗

PubMed1991

Motor activity of squirrel monkeys measured with an ultrasonic motion sensor.

We describe an ultrasonic motion sensing system for measuring the motor activity of individual squirrel monkeys in their home cage. The system utilizes an inexpensive Commodore 64 microcomputer for data collection and can distinguish between movements of short (i.e., less than 1.0 s) and longer (i.e., greater than or equal to 1.0 s) duration, and between number of movements and time spent in motion. The diurnal pattern of spontaneous activity is illustrated along with the dose-dependent effects of d-amphetamine (0.025-1.6 mg/kg) and haloperidol (0.025-0.4 mg/kg).

Animals↗