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Biomedical subjects

S G Holtzman

Publications and source records attributed to S G Holtzman.

At least 91 records · Page 5Linked to original sources
PubMed1991

Delta opioid antagonist, naltrindole, selectively blocks analgesia induced by DPDPE but not DAGO or morphine.

Initial reports suggest that naltrindole hydrochloride (NTI), a recently developed opioid, acts as a selective delta (delta) antagonist in vivo. Three experiments were conducted in rats to test NTI for its ability to dose-dependently and selectively block the analgesia produced by a delta-selective opioid agonist without affecting analgesia produced by mu (mu) receptor opioid agonists. Intracerebroventricular (ICV) administration of the delta-selective agonist, DPDPE (30 micrograms/rat), and the mu-selective agonist, DAGO (0.3 micrograms/rat), increased paw-lick latency (2-fold relative to baseline) in the hot-plate assay. NTI (0.01-1.0 micrograms/rat, ICV) dose-dependently attenuated DPDPE-induced analgesia (1.0 micrograms reduced paw-lick latency to baseline), but failed to affect DAGO-induced analgesia at any dose tested. A third experiment determined whether the ICV administration of NTI (1.0 micrograms/rat) would attenuate restraint stress-induced potentiation of morphine analgesia as indexed by the tail-flick assay. Rats that underwent 5 days of 1 h restraint stress and nonstressed rats were injected subcutaneously with morphine (1.0-8.0 mg/kg). The magnitude (greater than 2-fold) and duration of morphine-induced analgesia in restrained rats were significantly potentiated compared to nonstressed rats. NTI (1 microgram, ICV) failed to affect the magnitude and duration of morphine-induced analgesia regardless of restraint treatment. Thus, NTI failed to attenuate the analgesia produced by DAGO or morphine (in two assays of antinociception), whereas NTI (0.01-1.0 micrograms, ICV) antagonized dose-dependently DPDPE-induced analgesia. These results support the view that NTI is a selective delta-receptor antagonist in vivo.

Analgesia↗
PubMed1991

Effects of receptor-selective opioids on operant behavior in morphine-treated and untreated rats.

Selective cross-tolerance is often used as evidence to differentiate opioid receptor subtypes. We used this strategy to study operant behavioral effects of the opioid peptides, [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAGO), [D-Pen2.5]-enkephalin (DPDPE) and dynorphin, agonists highly selective for mu, delta, and kappa receptors, respectively. Food-deprived rats were trained to lever-press on a fixed-interval 3-min schedule of food-reinforcement. Time-effect and dose-effect curves were generated for each of the peptides, as well as for morphine, administered ICV, 5 min prior to the 1-h operant session. Experiments were performed on untreated subjects and on subjects receiving chronic infusion of morphine (10 mg/kg/day) from osmotic pumps. In untreated animals, morphine and the mu-selective peptide, DAGO, induced relatively long-lasting dose-related decreases in responding, whereas the non-mu agonists, DPDPE and dynorphin, induced only transient effects: response rates increased at low doses and decreased at high doses. Animals receiving chronic morphine infusion were tolerant to the rate-decreasing effects of morphine and DAGO; ED50s increased by factors of 8 and 6, respectively. There was some evidence of cross-tolerance to DPDPE and of sensitization to dynorphin in the morphine-maintained animals.

Animals↗
PubMed1991

Increased analgesic potency of mu agonists after continuous naloxone infusion in rats.

Chronic opioid antagonist administration increases opioid binding sites and potentiates behavioral responses to morphine. The present study was designed to examine in rats the temporal and dosage parameters of naloxone-induced potentiation of morphine analgesia and the effect of continuous infusion of naloxone on the analgesic potency of other mu agonists. Cumulative dose-response curves were generated in a tail-flick procedure for each drug tested. Naloxone-filled osmotic pumps were then implanted s.c. for 1 week after which the rats were retested with the agonist. The potency ratio of morphine (ED50 before naloxone/ED50 after naloxone) showed orderly increases over a range of naloxone doses (0.03-1.0 mg/kg/hr) and increased, then decreased, over a range of time points (6-72 hr) after removal of the osmotic pumps. The relative potency of morphine was 2.1 at 24 hr after a 7-day infusion of 0.3 mg/kg/hr of naloxone. These parameters were then used in tests of other mu agonists. Five drugs produced maximum increases in tail-flick latencies before naloxone. Of these, naloxone increased the analgesic potency of fentanyl, methadone and levorphanol (relative potencies ranged from 1.7-2.1) but not of etorphine and propoxyphene. The naloxone infusion increased the maximum analgesic effect of meperidine, profadol and pentazocine, but had no effect on the analgesic activity of buprenorphine, butorphanol, ethylketocyclazocine and nalbuphine. Our results demonstrate that 7-day naloxone infusion increases the analgesic potency of some, but not all, opioids with mu agonist activity.

Analgesia↗
PubMed1991

Role of adenosine receptors in caffeine tolerance.

Caffeine is a competitive antagonist at adenosine receptors. Receptor up-regulation during chronic drug treatment has been proposed to be the mechanism of tolerance to the behavioral stimulant effects of caffeine. This study reassessed the role of adenosine receptors in caffeine tolerance. Separate groups of rats were given scheduled access to drinking bottles containing plain tap water or a 0.1% solution of caffeine. Daily drug intake averaged 60-75 mg/kg and resulted in complete tolerance to caffeine-induced stimulation of locomotor activity, which could not be surmounted by increasing the dose of caffeine. 5'-N-ethylcarboxamidoadenosine (0.001-1.0 mg/kg) dose dependently decreased the locomotor activity of caffeine-tolerant rats and their water-treated controls but was 8-fold more potent in the latter group. Caffeine (1.0-10 mg/kg) injected concurrently with 5-N-ethylcarboxamidoadenosine antagonized the decreases in locomotor activity comparably in both groups. Apparent pA2 values for tolerant and control rats also were comparable: 5.05 and 5.11. Thus, the adenosine-antagonist activity of caffeine was undiminished in tolerant rats. The effects of chronic caffeine administration on parameters of adenosine receptor binding and function were measured in cerebral cortex. There were no differences between brain tissue from control and caffeine-treated rats in number and affinity of adenosine binding sites or in receptor-mediated increases (A2 adenosine receptor) and decreases (A1 adenosine receptor) in cAMP accumulation. These results are consistent with theoretical arguments that changes in receptor density should not affect the potency of a competitive antagonist. Experimental evidence and theoretical considerations indicate that up-regulation of adenosine receptors is not the mechanism of tolerance to caffeine-induced stimulation of locomotor activity.

Adenosine↗
PubMed1991

Qualitative differences in the discriminative stimulus effects of low and high doses of caffeine in the rat.

Caffeine engenders qualitatively different subjective effects in humans at low and high doses. Low doses of caffeine are mildly reinforcing and produce psychomotor stimulation. High doses of caffeine can produce subjective feelings of anxiety, dysphoria and depression. The present study was designed to model these different subjective states in rats using a discrete trial shock avoidance/escape drug discrimination paradigm. Rats were trained to discriminate between i.p. injections of saline and either 10 or 56 mg/kg of caffeine. Rats trained at 10 mg/kg of caffeine acquired the discrimination in an average of 93 sessions and generalized completely to a variety of xanthine and nonxanthine behavioral stimulants including: d-amphetamine, apomorphine, 7-(beta-chloroethyl)theophylline, 9-chloro-2-(2-furanyl)-5,6-dihydro-1, 2,4-triazolo[1,5-c]quinazolin-5-imine (CGS 15943), cocaine, 1,7-dimethylxanthine, diethylpropion, beta-hydroxyethyltheophylline, methylphenidate, phenidimetrazine and theophylline. Rats trained at 56 mg/kg of caffeine acquired the discrimination in an average of 43 sessions and generalized completely only to theophylline. A variety of drugs representing diverse pharmacologic classifications including: benzodiazepine inverse agonists, pentylenetetrazol, yohimbine, ethylketocyclazocine and phencyclidine, were not generalized from either training dose, demonstrating the pharmacologic specificity of the discrimination. The discriminative effects of 10 mg/kg of caffeine appear to derive from a state of behavioral arousal, possibly mediated by catecholamines, and parallel the subjective effects produced by low doses of caffeine in humans. The discriminative effects of 56 mg/kg of caffeine are qualitatively different from those of 10 mg/kg but cannot be defined further at this time.

Adenosine↗
PubMed1990

Factors affecting restraint stress-induced potentiation of morphine analgesia.

The analgesic effect of opioid drugs is potentiated in rats exposed to restraint stress as compared to unstressed rats. The purpose of the present study was to quantify how the following factors affect morphine-induced analgesia: habituation to restraint versus exposure to restraint for the first time, restraint stress duration, and interval from restraint to analgesic testing. Expts. 1 and 2 generated dose- and time course curves for morphine in rats exposed to one of 3 treatments: no restraint stress (NS), first exposure to 1 or 6 h of restraint (FS), or 5 days of restraint habituation followed by 1 or 6 h of restraint on the test day (HAB). Analgesia was measured by the tail-flick assay. Rats subjected to 1 h of restraint displayed dose- and time-dependent potentiation of morphine-induced antinociception compared to unstressed rats. Given 4.0 mg/kg morphine. FS-treated subjects showed 1.4- and 2.7-fold more potentiation of analgesia than HAB- and NS-treated rats, respectively. Rats restrained for 6 h prior to testing showed significant dose effect for morphine but failed to reveal significant treatment effects. Thus, increasing the duration of restraint from 1 to 6 h attenuated morphine antinociception in FS- and HAB-treated subjects to the level of NS subjects. In Expt. 3, several groups of rats underwent a single 1-h session of restraint at various time intervals prior to injection with morphine (4.0 mg/kg) and tail-flick testing. An unstressed group also receiving morphine served as control.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1990

Methylxanthines elevate reinforcement threshold for electrical brain stimulation: role of adenosine receptors and phosphodiesterase inhibition.

Caffeine increases reinforcement threshold in a brain stimulation procedure that allows the rat to self-regulate the intensity of electric current delivered via an electrode in the medial forebrain bundle. In order to determine the generality of that finding, we used this same autotitration procedure to assess the behavioral effects of 5 methylxanthines in addition to caffeine. All of the methylxanthines produced significant dose-dependent elevations of reinforcement threshold with the following order of potency: 7-(beta-chloroethyl)theophylline greater than isobutylmethyl-xanthine greater than 1,7-dimethylxanthine greater than theophylline greater than caffeine greater than 8-chlorotheophylline. This order of potency correlates significantly with the reported order of potency for inhibiting adenosine-stimulated cAMP, an effect mediated by the adenosine A2 receptor. Some of the behavioral effects of methylxanthines have been attributed to antagonism of adenosine receptor binding and inhibition of phosphodiesterase. The nonxanthine phosphodiesterase inhibitors papaverine and Ro 20-1724, had small but significant effects on reinforcement threshold, papaverine increasing it and Ro 20-1724 decreasing it. Thus, as a pharmacologic class, methylxanthines appear to increase reinforcement threshold, an effect which may be mediated via adenosine receptor antagonism but probably not by inhibition of phosphodiesterase.

Animals↗
PubMed1990

Stress-induced tolerance to delta receptor agonist DPDPE and selectivity of the irreversible delta-ligand, DALCE.

Experiments were conducted to (1) provide further evidence of the selectivity of [D-Ala2,Leu5,Cys6]enkephalin (DALCE) as an antagonist of delta (delta) receptor ligands and (2) use DALCE as a tool to explore the possible role of delta receptors in restraint stress. Dose- and time-response curves were generated for the respective delta- and mu (mu)-selective opioid agonists DPDPE (3-30 micrograms) and DAGO (0.03-0.3 microgram) to increase the latency to paw-lick in the hot-plate test in rats. Both agonists produced robust analgesia lasting at least 20 min when injected intracerebroventricularly (i.c.v.). DALCE (0.4-10 micrograms) administered i.c.v. 24 h earlier failed to affect baseline pain sensitivity. DALCE pretreatment dose-dependently blocked the increase in paw-lick latency produced by DPDPE (30 micrograms) but not that induced by an equivalent analgesic dose of DAGO (0.3 microgram). In the last experiment we determined whether 1 h of restraint stress would (a) alter delta receptor sensitivity as indexed by DPDPE-induced analgesia and (b) attenuate the ability of DALCE to functionally antagonize DPDPE-induced analgesia. Rats were assigned to one of four treatment groups: i.c.v. vehicle injection/no stress; vehicle/stress; i.c.v. DALCE (10 micrograms)/no stress; DALCE/stress. Twenty-four hours after treatment, dose- and time-response curves were generated to test the ability of DPDPE (30-120 micrograms) to increase paw-lick latency. Prior exposure to stress alone produced tolerance to DPDPE-induced analgesia. DALCE pretreatment antagonized DPDPE similarly regardless of stress condition. The effects of both stress and DALCE were surmounted by the highest dose of DPDPE.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1990

Tolerance and dependence after continuous morphine infusion from osmotic pumps measured by operant responding in rats.

Food-deprived rats were trained to lever-press on a fixed interval 3-min schedule of food presentation. Using a cumulative dosing procedure, morphine and naltrexone were tested weekly for effects on rates of responding. A separate group of subjects was tested weekly for morphine analgesia using the tail-flick assay. Chronic morphine infusion (10 mg/kg/day, SC, from a 4-week osmotic pump) induced tolerance to the rate-decreasing and analgesic effects of morphine as demonstrated by a more than 4-fold increase in the morphine ED50s for both of these effects, relative to those of predependent rats. Physical dependence was evidenced in the operant procedure by increased sensitivity to the rate-decreasing effects of the opioid antagonist, naltrexone, such that the ED50 for naltrexone was 5000 times lower than it was in predependent animals. In addition, marked weight loss was observed over the 2-h naltrexone test session. The degree of tolerance was a function of both the length of chronic administration and of the maintenance dose and was of a similar magnitude for operant responding and analgesia. Further, the degree of tolerance and dependence was comparable to that observed in other studies that used different methods of chronic drug administration. Thus, osmotic pumps provide a convenient and effective alternative for chronic drug administration in behavioral studies.

Analgesics↗
PubMed1990

Depletion of catecholamines in the brain of rats differentially affects stimulation of locomotor activity by caffeine, D-amphetamine, and methylphenidate.

The purpose of this study was to assess the role of catecholamines in brain, in the stimulation of locomotor activity, induced by caffeine, as compared to the psychomotor stimulants D-amphetamine and methylphenidate. Adult male rats were pretreated with either (1) 2.5 mg/kg (i.p.) reserpine, 24 hr prior to testing of locomotor activity, (2) 50 mg/kg (i.p.) alpha-methyl-para-tyrosine (AMPT) 6 hr and 2 hr prior to testing of locomotor activity, (3) 200 micrograms/rat (i.c.v.) 6-hydroxydopamine (6-OHDA), or 25 mg/kg (i.p.) desmethylimipramine (DMI) and 200 micrograms/rat 6-OHDA (i.c.v.), 6-8 weeks prior to testing. Each treatment group had a matched control group. Levels of catecholamines in the forebrain were determined in each of the treatment and corresponding control groups. All rats were tested with doses of caffeine, D-amphetamine and methylphenidate (excluding the 6-OHDA-treated animals), administered in random order intraperitoneally 35 min before locomotor activity was measured for 30 min. Pretreatment with either reserpine or AMPT attenuated the stimulation of locomotor activity induced by caffeine and D-amphetamine but not that induced by methylphenidate. The dose-response curve for amphetamine was shifted downward and to the right by reserpine but was flattened by AMPT. The dose-response curve for caffeine was displaced downward in a similar manner by both reserpine and AMPT. Treatment with 6-OHDA or DMI + 6-OHDA produced the expected changes in the content of catecholamines in brain, but failed to modify dose-response curves for caffeine or amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacological profile of the potentiation of opioid analgesia by restraint stress.

Morphine-treated rats exposed to restraint stress show potentiated magnitude and duration of analgesia compared to unstressed rats. The present study was performed to assess the pharmacological characteristics of stress-induced potentiation of opioid analgesia. We tested 10 opioids to determine whether restraint stress treatment would potentiate their ability to produce antinociception indexed by the tail-flick assay. We tested full mu, delta and kappa opioid receptor agonists (fentanyl, meperidine, DPDPE, U50488H, ethylketocyclazocine), and mixed agonist/antagonists representing a range of receptor selectivities and intrinsic activities (profadol, buprenorphine, pentazocine, butorphanol and nalbuphine). Dose-effect and time-response curves were generated for unrestrained and restrained rats after either subcutaneous (SC) and/or intracerebroventricular (ICV) injections. In restrained rats, all drugs except for SC-administered nalbuphine produced dose- and time-dependent analgesic effects of greater magnitude (1.5-3 times) than they produced in unrestrained rats. However, restrained rats given agonists with high intrinsic activity at the mu receptor displayed the most potent and consistent potentiation of analgesia compared to unrestrained controls. Our results suggest that activation of the mu receptor is of primary importance for restraint to potentiate analgesia, because restrained rats injected with delta and kappa agonists displayed potentiation of analgesia only at doses high enough to possibly exceed the selective activation of their respective receptor types.

Animals↗
PubMed1990

Assessment of relative intrinsic activity of mu-opioid analgesics in vivo by using beta-funaltrexamine.

Morphine is the prototypic mu-opioid analgesic; however, in certain situations in vitro, morphine behaves as a partial agonist. To assess the relative intrinsic activity of morphine and three other mu-opioid analgesics in vivo, beta-funaltrexamine (beta-FNA), an irreversible antagonist selective for the mu receptor, was used to reduce the effective receptor reserve. By using a stereotaxic device, 1.25 to 20 micrograms of beta-FNA was infused into the lateral ventricle of rats. Twenty-four hours later, animals were tested in the tail-flick assay with cumulative doses of morphine, levorphanol, methadone or fentanyl. Pretreatment with 2.5 micrograms of beta-FNA induced parallel rightward shifts of both the morphine and levorphanol dose-effect curves and 5.0 micrograms of beta-FNA reduced the maximum analgesic effect of these agonists. Methadone surmounted the antagonism of 5.0 micrograms of beta-FNA; 10 micrograms was required to reduce the maximum analgesic effect of methadone. Fentanyl overcame the blockade induced by both 5.0 and 10 micrograms of beta-FNA. Only with a pretreatment dose of 20 micrograms of beta-FNA was the maximum analgesic effect of fentanyl reduced. Thus, when a certain proportion of mu receptors is inactivated, i.e., with 5.0 micrograms of beta-FNA, fentanyl and methadone have the capacity to surmount the blockade, whereas morphine and levorphanol do not. This suggests that fentanyl and methadone have higher intrinsic efficacies than do morphine and levorphanol. Thus, a strategy used widely in vitro was applied successfully in vivo to assess relative intrinsic activities of a series of mu-opioid agonists.

Analgesics↗
PubMed1990

Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats.

The pharmacologic specificity of the sensitization to naltrexone induced by acute opioid pretreatment was studied in rats trained to lever-press on a multiple-trial, fixed-interval 3-min schedule of food reinforcement. Cumulative doses of naltrexone were given until responding was suppressed; control naltrexone ED50 values for decreasing response rates ranged from 5.0 to 22 mg/kg. Agonists were administered 4 hr before naltrexone challenge. Pretreatment with morphine (10 mg/kg) initially produced a 4-fold shift to the left of the naltrexone dose-effect curve, but after repeated weekly testing with various agonists, produced a 1700-fold shift. Pretreatment with other millimicrons agonists (i.e., 0.3 mg/kg of levorphanol, 0.06 mg/kg of fentanyl and 3.0 mg/kg of methadone) produced similarly large (100- to 250-fold) increases in sensitivity to the rate-decreasing effects of naltrexone. On the other hand, pretreatment with agonists selective for kappa (1.0 mg/kg of ethylketocyclazocine and 3.0 mg/kg of U-50,488) or sigma (10 mg/kg of [+]-N-allylnormetazocine) receptors, produced smaller (10-fold) changes in sensitization to naltrexone. Neither dextrorphan (3.0 mg/kg) nor pentobarbital (18 mg/kg) pretreatment altered sensitivity to naltrexone. Thus, the sensitization to naltrexone induced by acute opioid pretreatment was a stereoselective, opioid-specific effect, and appeared to be mediated primarily by a mu-opioid mechanism. With repeated testing, the effect of acute morphine pretreatment was comparable to that reported after chronic administration, thus supporting the hypothesis that this phenomenon reflects receptor-mediated changes that underlie the state of opioid physical dependence.

Animals↗
PubMed1989

Stress-induced potentiation of morphine-induced analgesia in morphine-tolerant rats.

This study was designed to evaluate whether or not rats that were tolerant to the analgesic action of morphine were also tolerant to stress-induced potentiation of morphine-induced analgesia. Rats were trained to drink either solutions of morphine (0.5 mg/ml) or drug-free tap water on a limited access schedule (10 min every 6 hr). The daily intake of morphine averaged 46 mg/kg. Nontolerant and rats tolerant to morphine were tested for morphine-induced analgesia (tail-flick assay), while either unstressed or stressed (i.e. immobilized in Plexiglas cylinders). Morphine produced dose- and time-dependent increases in tail-flick latencies in all groups. Increased sensitivity to analgesia induced by morphine was evident for both nontolerant and tolerant, stressed rats, when compared to their unstressed counterparts. Stress-induced potentiation of morphine-induced analgesia was characterized by dose-related increases in the peak effect and duration of the effect. Stress potentiated the analgesic effect of morphine, comparably in nontolerant (1.7-fold) and tolerant (1.5-fold) rats. Differential tolerance to analgesia induced by morphine and to stress-induced potentiation of morphine-induced analgesia suggests that different mechanisms mediate these two effects.

Analgesics, Opioid↗
PubMed1989

Phosphodiesterase inhibitors potentiate opiate-antagonist discrimination by morphine-dependent rats.

This study was performed to examine the relevance of the quasi-withdrawal syndrome in nondependent rats to the syndrome precipitated by naltrexone in rats physically dependent upon morphine. Morphine-dependent rats trained to discriminate between SC injections of naltrexone (0.1 mg/kg) and saline were pretreated with 10 mg/kg of a phosphodiesterase inhibitor: 3-isobutyl-1-methylxanthine (IBMX), Ro 20-1724, or papaverine. The naltrexone stimulus-generalization curve and dose-response curve for loss of body weight were shifted to the left by IBMX and Ro 20-1724, which produce quasi-withdrawal, but not by papaverine, which does not. IBMX also potentiated the naltrexone-like discriminative effects and loss of body weight induced by cyclazocine, an opioid agonist-antagonist. Butorphanol, another agonist-antagonist, occasioned choice responding appropriate for saline when tested alone but engendered more than 50% naltrexone-appropriate choice responses in rats pretreated with IBMX. Thus, phosphodiesterase inhibitors that produce an opiate quasi-withdrawal syndrome potentiate interoceptive stimuli and weight loss associated with the withdrawal syndrome precipitated by naltrexone in morphine-dependent rats. Furthermore, they appear to enhance the opiate-antagonist activity of opioids with mixed agonist and antagonist properties.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Opioid- and phencyclidine-like discriminative effects of ditolylguanidine, a selective sigma ligand.

The sigma binding site in brain has affinity for psychotomimetic opioids, phencyclidine (PCP) and antipsychotic drugs, and is a separate entity from the PCP receptor. In order to demonstrate a behavioral correlate of sigma binding, rats were trained to discriminate between s.c. injections of saline and 3.0 mg/kg of ditolylguanidine (DTG), a selective and high affinity sigma ligand, and tested for generalization to novel drugs. The rats generalized dose dependently and completely or almost completely to PCP and related drugs and to mu, kappa and sigma opioid agonists. A separate group of rats trained to discriminate saline from 2.0 mg/kg of PCP generalized completely to DTG, confirming the commonalities in the discriminative effects of these drugs. DTG-like discriminative effects of opioid enantiomers showed no consistent stereoselectivity. Discriminative effects of the DTG training dose were neither mimicked by haloperidol and (-)-butaclamol, which have high affinity for the sigma site, or by the opioid antagonist naltrexone. Order of potency in producing DTG-like discriminative effects did not correlate with published reports of relative drug affinity for the sigma site or the PCP receptor. Although the discriminative effects of DTG have commonalities with those of several types of opioid and PCP-like drugs, their pharmacologic characteristics are different from the pharmacologic characteristics of opioid and PCP receptors as well as from those of the sigma binding site.

Animals↗
PubMed1988

Effects of intrahypothalamic administration of opioid peptides selective for mu-, kappa, and delta-receptors on different schedules of water intake in the rat.

The effects of opioid peptides selective for mu, kappa, and delta-opioid receptors were investigated on 3 different schedules of water intake in the rat: spontaneous, deprivational (12 h), and hypertonic saline-induced drinking. Peptides were injected into the paraventricular and supraoptic hypothalamic nuclei, D-Ala2-NMePhe4-Gly(ol)-enkephalin, a mu-selective opioid agonist, tended to increase water intake in non-deprived rats, but 0.01 and 0.1 microgram significantly decreased water intake for 45 min in deprived rats, and for up to 60 min in hypertonic saline-injected rats when injected into the paraventricular hypothalamic nucleus. The kappa-selective agonist, dynorphin A1-13 (0.1, 0.3, 1.0 and 3.0 micrograms)and the delta-selective agonist, [D-Pen2,L-Pen5]enkephalin (0.3 and 3.0 micrograms) did not affect spontaneous, deprivational or hypertonic saline-induced water intakes when injected into either the paraventricular or supraoptic hypothalamic nuclei. Thus, a mu-selective opioid peptide produced dose- and time-dependent effects on drinking that were pharmacologically and anatomically specific, and dependent upon the schedule of water intake.

Animals↗