Biomedical subjects

G A Tejwani

Publications and source records attributed to G A Tejwani.

At least 19 recordsLinked to original sources

PubMed2000

Glutamate receptors participate in the nicotine-induced changes of met-enkephalin in striatum.

A single dose of nicotine given to mice induces first a rapid decrease (presumed release/enhanced degradation) and then a rise (presumed synthesis/enhanced accumulation) of met-enkephalin (Met-Enk) in dorsal and ventral striatum observed at 30 and 60 min post-treatment, respectively. These studies investigated whether the nicotine effect on Met-Enk was mediated indirectly, in part, via other neurotransmitters known to be released by nicotine. Based on the ability of selective antagonists of dopamine (Sch 23390, D1; Sulpiride, D2), glutamate (CPP, competitive NMDA; dizocilpine, non-competitive NMDA; NBQX, AMPA) and GABA (bicuculline, GABA(A); Sch 50911, GABA(B)) receptors, to inhibit or enhance the response to nicotine, we conclude that nicotine alters striatal Met-Enk, in part, via glutamate NMDA and AMPA receptors. These findings further support the notion that glutamate might play a role in the pharmacology of nicotine.

Animals↗

PubMed2000

Antagonism of antinociception produced by intrathecal clonidine by ketorolac in the rat: the role of the opioid system.

The management of severe pain may require "balanced analgesia," involving the use of analgesics with different modes of action. Clonidine, an alpha(2)-adrenoreceptor agonist produces analgesia by itself as well as when given with morphine and local anesthetics. Ketorolac is indicated for the management of moderately severe acute pain and causes analgesia equivalent to morphine. This study was designed to investigate whether the addition of ketorolac promotes antinociception produced by intrathecal administration of clonidine in male Sprague-Dawley rats. Intrathecal injection of clonidine (1-30 microg) induced a dose-dependent increase in antinociception as measured by the tail flick (TF) and hot plate tests. Ketorolac alone (150-600 microg) increased the antinociception by 50%-60% only in the TF test. Ketorolac (10 microg) decreased clonidine (10 microg)-induced antinociception from 69.1% +/- 7.8% to 23.5% +/- 1. 6% (P < 0.05) in the TF test and 35.7% +/- 4.7% to 4.5% +/- 0.1% (P < 0.05) maximum possible effect in the hot plate test. Ketorolac also antagonized the effect of 30 microg of clonidine. The opioid receptor antagonist naloxone antagonized the antinociceptive effect of clonidine and ketorolac, indicating the involvement of the opioid system in the antinociception produced by clonidine or ketorolac. However, neither clonidine nor ketorolac (10(-8) to 10(-3) M) inhibited the binding of specific ligands to mu-, delta-, and kappa-opioid receptors, indicating a lack of direct interaction of clonidine and ketorolac with opioid receptors. These results suggest that intrathecal injection of ketorolac antagonizes the antinociception produced by clonidine.

Adrenergic alpha-Agonists↗

PubMed1999

The effect of chronic administration of nicotine on antinociception, opioid receptor binding and met-enkelphalin levels in rats.

The effect of chronic nicotine administration on (1) antinociception; (2) opioid receptor binding; and (3) met-enkelphalin levels in discrete brain regions in rats was investigated. Male and female Sprague-Dawley rats were treated with nicotine 0.3 mg/kg, 0.1 mg/kg, or saline three times a day subcutaneously during a 14-day protocol. Antinociception was measured by hotplate (HP) test on days 1, 2, 7, 10 and 14. After completion of the protocol, mu-opioid receptors were analyzed by [3H]-DAMGO binding studies and met-enkelphalin levels were determined by radioimmunoassay. Results indicated that hot-plate latency increased during the first 2 days of nicotine administration for male and female rats who were treated with 0.3 mg/kg nicotine. There was an up-regulation of mu-receptors (increased Bmax) in the striatum of rats treated with 0.3 mg/kg nicotine, compared to 0. 1 mg/kg nicotine and saline groups. An interaction effect of group by gender was noted. After 14 days of chronic nicotine administration, met-enkelphalin levels were significantly lower in striatum and midbrain of animals treated with 0.3 mg/kg nicotine, as compared to controls. These results suggest that chronic nicotine administration, in doses representative of human smoking, produces antinociception initially, and is accompanied by an upregulation of micro-opioid receptors in the striatum of rats. In addition, nicotine-induced tolerance to antinociception may be associated with a decrease in met-enkelphalin level over a period of time.

Analgesics, Opioid↗

PubMed1999

Decreased neuropeptide content in the spinal cord of aged rats: the effect of GM1 ganglioside.

This study investigated the status of substance P (SP), methionine-enkephalin (Met-Enk) and dynorphin A(1-13) (Dyn A) in the spinal cord of aged Sprague-Dawley rats and the effect of GM1 ganglioside on these neuropeptides. SP and Met-Enk, but not Dyn A, were decreased in both dorsal and ventral horns of the aged spinal cord. Treatment with GM1 ganglioside (30 mg/kg i.p., daily for 30 days) restored, in part, the neuropeptide deficits in the ventral horns, but not in the dorsal horns. This information might be important for understanding the sensory and motor deficits associated with ageing, and how the spinal cord neuropeptides might be amplified in the aged spinal cord.

Aging↗

PubMed1998

Inhibition of morphine tolerance and dependence by diazepam and its relation to mu-opioid receptors in the rat brain and spinal cord.

We have recently observed that concomitant administration of diazepam to morphine pellet implanted rats results in the inhibition of the development of morphine tolerance and dependence. We have now analyzed mu-opioid receptors in rats treated with morphine and diazepam for 5 days by using [3H]-DAMGO for binding studies. Male Sprague-Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b.wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5). There was an up-regulation of mu-receptor (Bmax increased) in the spinal cord of morphine tolerant (+139%) and dependent (+155%) rats compared to saline treated animals. Diazepam treatment abolished the up-regulation of mu-receptors in spinal cord of morphine treated rats. In the cortex, Bmax was not affected in morphine tolerant or dependent rats but it decreased by 38% in morphine tolerant and 65% in morphine dependent rats treated with diazepam. The Kd of mu-receptors increased in the cortex, striatum and hypothalamus of morphine dependent rats. Diazepam treatment decreased the Kd of mu-receptors in the cortex of morphine tolerant and hypothalamus of morphine-dependent rats. These results suggest that diazepam treatment antagonizes the up-regulation of CNS mu-receptors observed in morphine tolerant rats. In addition, morphine tolerance and dependence may be associated with conversion of mu-opioid receptors to mu-constitutive opioid receptors that are less active, and this conversion is prevented in the brain of animals treated with diazepam.

Analgesics, Opioid↗

PubMed1998

Naltrexone administration affects ad libitum smoking behavior.

Endogenous opioid peptides have been implicated in the reinforcement of smoking and opioid antagonists have been examined to determine their role in smoking behavior. To date, the relationship between smoking behavior and chronic opiate antagonist administration during ad libitum smoking has not been investigated. The purpose of this study was to examine the relationships between naltrexone, an opiate antagonist administered orally, and smoking behavior and mood states during ad libitum smoking. A repeated measures experimental design was used. Normal adult male and female volunteers, admitted to the Clinical Research Center, were randomly assigned to naltrexone-treated (n = 22) or placebo-control (n = 21) groups in a double-blind manner. Day 1 was considered acclimation to the unit and day 2 was baseline, or pre-drug administration. On days 3, 4, and 5, subjects received 50 mg naltrexone or a placebo at 0700 and 1600 hours. Plasma nicotine and expired air carbon monoxide levels were measured daily at 1900 hours. Number of cigarettes smoked, mood states, withdrawal symptomatology and self-reported satisfaction with smoking were also quantified daily. Results indicated that plasma nicotine levels (P = 0.005), number of cigarettes smoked daily (P = 0.003) and self-reported satisfaction with smoking (P = 0.043) were significantly lower among those treated with naltrexone, compared to the placebo-control group. Expired air carbon monoxide levels did not differ between the two groups. In addition, mood states and withdrawal symptoms did not differ between groups. These findings suggest that endogenous opioid peptides influence specific smoking behavior variables.

Adult↗

PubMed1997

Met-enkephalin alteration in the rat during chronic injection of morphine and/or midazolam.

We have recently reported that the short-acting anesthetic and analgesic drug midazolam can produce analgesia and decrease morphine tolerance and dependence in the rat by interacting with the opioid system. This study was designed to investigate the effect of midazolam, morphine, and both together on met-enkephalin levels in the rat. Male Sprague-Dawley rats were divided into four groups: (1) saline-saline; (2) saline-morphine; (3) midazolam-saline, and (4) midazolam-morphine groups. First, a saline or midazolam injection was given intraperitoneally and after 30 min a second injection of saline or morphine was given subcutaneously once daily for 11 days. Animals were sacrificed on the 11th day 60 min after the last injection to measure met-enkephalin by radioimmunoassay. Morphine tolerant animals showed a significant increase in met-enkephalin levels in the cortex (137%) and midbrain (89%), and a significant decrease in met-enkephalin levels in the pituitary (74%), cerebellum (34%) and medulla (72%). Midazolam treated animals showed a significant decrease in met-enkephalin levels in the pituitary (63%), cortex (39%), medulla (58%), kidneys (36%), heart (36%) and adrenals (43%), and a significant increase in met-enkephalin levels in the striatum (54%) and pons (51%). When morphine and midazolam were injected together, midazolam antagonized the increase in met-enkephalin levels in cortex and midbrain region and the decrease in met-enkephalin level in the medulla region observed in morphine tolerant animals. These results indicate that morphine tolerance and dependence is associated with changes in the concentration of met-enkephalin in the brain. Midazolam may inhibit morphine tolerance and dependence by reversing some of the changes induced in met-enkephalin levels in brain by morphine in morphine tolerant and dependent animals.

Animals↗

PubMed1997

Effect of chronic treatment with morphine, midazolam and both together on dynorphin(1-13) levels in the rat.

We have recently reported that midazolam, a benzodiazepine receptor agonist that is also a short acting anesthetic and analgesic drug, can produce analgesia and decrease morphine tolerance and dependence in the rat by interacting with the opioidergic system. This study was designed to investigate the chronic effect of midazolam and/or morphine on the levels of dynorphin(1-13) in the pituitary gland, different brain regions, spinal cord and peripheral tissues of the rat. Four sets of animals were used: (I) saline-saline; (II) midazolam (0.03, 0.3 or 3.0 mg/kg, body wt., i.p.)-saline; (III) saline-morphine (10.0 mg/kg, body wt., s.c.); and (IV) midazolam-morphine (0.03, 0.3 or 3.0 mg/kg midazolam + 10.0 mg/kg morphine) groups. The first saline or midazolam injection was given i.p. and after 30 min, the second injection of saline or morphine was given s.c. daily for 11 days. Animals were sacrificed on the 11th day, 60 min after the last injection and dynorphin(1-13) was measured in indicated tissues by radioimmunoassay method. The midazolam treated animals showed a significant decrease in dynorphin(1-13) levels in the cortex, cerebellum, cervical region of spinal cord, heart and adrenals, and a significant increase in the hypothalamus, striatum and lumbar region of the spinal cord. The morphine treated animals showed a significant decrease in dynorphin(1-13) levels in the pituitary gland, hypothalamus, hippocampus, striatum, cerebellum, pons, medulla, kidneys, adrenals and spleen, and a significant increase only in the lumbar region of the spinal cord. When both drugs were injected together there was no effect on pituitary gland, kidneys and spleen. These drugs antagonize each other's effect on dynorphin(1-13) in the hypothalamus, striatum, cerebellum, pons, medulla and heart. However, the midazolam-morphine combination significantly increases dynorphin(1-13) levels in the hippocampus, cortex, midbrain, cervical and lumbar regions of the spinal cord, and adrenals. These results suggest the involvement of dynorphin(1-13) in the inhibition of morphine-induced tolerance and dependence by midazolam in the rat. These results may also help us in understanding the intrinsic mechanisms involved in narcotic tolerance and dependence.

Adrenal Glands↗

PubMed1996

Effect of chronic treatment with morphine, midazolam, and both together on beta-endorphin levels in the rat.

We have recently reported that a short-acting anesthetic and analgesic drug midazolam can produce analgesia and decrease morphine tolerance and dependence in the rat by interacting with the opioid system. This study was designed to investigate the effect of midazolam, morphine, and both together on beta-endorphin levels in the rat. Male Sprague-Dawley rats were divided into four groups: (1) saline-saline; (2) saline-morphine; (3) midazolam-saline, and (4) midazolam-morphine groups. First, saline or midazolam injection was given IP and after 30 min a second injection of saline or morphine was given subcutaneously once daily for 11 days. Animals were sacrificed on 11th day 60 min after the last injection, to measure beta-endorphin by radioimmunoassay. Saline-morphine-treated animals showed a significant increase in beta-endorphin levels in the cortex, pons, medulla, lumbar spinal cord, adrenals, and spleen, and a decrease only in its level in pituitary. Midazolam-saline-treated animals showed a significant increase in beta-endorphin levels only in the medulla, and a decrease in its levels in hippocampus, striatum, and adrenals. Saline-morphine-treated animals did not show any changes in plasma beta-endorphin, but animals treated with midazolam-saline had a significant decrease in plasma beta-endorphin. In rats treated with morphine and midazolam together, beta-endorphin levels in cortex, lumbar spinal cord, and spleen decreased to the similar levels observed in rats treated with saline-saline; in pons and cervical spinal cord the levels were even lower than that found in saline-saline group. The decrease in pituitary beta-endorphin in morphine-midazolam-treated rats was due to morphine's own activity, whereas the decrease in plasma beta-endorphin in hippocampus in the morphine-midazolam group was a synergistic effect of morphine and midazolam. The beta-endorphin level in adrenal glands in the morphine-midazolam-treated animals was not different from that found in rats treated with morphine alone but was still higher than that in the saline-saline group. In general, it appears that chronic treatment with morphine stimulates the beta-endorphinergic system. A concomitant treatment with midazolam abolishes the stimulatory effect of morphine on the beta-endorphinergic system. These results may help us in understanding the intrinsic mechanisms involved in narcotic tolerance and dependence.

Animals↗

PubMed1995

Inhibition of morphine tolerance and dependence by diazepam and its relation to cyclic AMP levels in discrete rat brain regions and spinal cord.

Diazepam inhibits morphine tolerance and dependence and reverses a decrease in the met-enkephalin level in brain induced by morphine. In this study, we investigated whether inhibition of morphine-induced tolerance and dependence by diazepam involved a change in cyclic AMP levels in discrete rat brain regions and spinal cord. Male Sprague-Dawley rats were made tolerant and dependent by subcutaneous (s.c.) implantation of six morphine pellets (two pellets on the first day, and four on the second day). Diazepam (0.25 mg/kg b. wt) was injected once daily intraperitoneally (i.p.) for 5 days. Control rats were implanted with placebo pellets and injected once daily with saline or diazepam (i.p.). Tail-flick antinociception was measured 1 h after injections everyday. Animals were administered s.c. naloxone (10 mg/kg) to induce naloxone-precipitated withdrawal syndrome on the final day of the experiment (day 5), and the jumping behavior was observed for 30 min. Concomitant treatment with diazepam (0.25 mg/kg) significantly decreased the development of morphine tolerance and dependence. Diazepam (0.25 mg/kg) treated rats also showed a significant decrease in the jumping behavior compared to animals treated with morphine alone. Rats were sacrificed 2 h after the injection of saline or diazepam (0.25 mg/kg) on the fifth day. Cyclic AMP was estimated by RIA. In the control rats, the concentration of cyclic AMP in cortex was > hippocampus > cerebellum > hypothalamus > striatum > midbrain > pituitary > pons/medulla > spinal cord. There was no change in the concentration of cyclic AMP in any of the brain regions examined from morphine tolerant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Preproenkephalin mRNA and methionine-enkephalin content are increased in mouse striatum after treatment with nicotine.

A single dose of nicotine increased methionine-enkephalin (Met-Enk) immunoreactivity in the striatum of mice in a time-dependent manner. Met-Enk content reached maximum by approximately 1 h after nicotine and returned to control values by 6 h. The response to nicotine was blocked by pretreating animals with the nicotinic receptor antagonist mecamylamine. In contrast, pretreating mice with the muscarinic receptor antagonist atropine or the dopamine receptor antagonist haloperidol did not block the response. A single dose of nicotine also increased mRNA for the precursor peptide preproenkephalin (PPE). The increase of PPE mRNA preceded that of Met-Enk and reached a maximum by approximately 30 min after nicotine. PPE mRNA levels returned to near normal by approximately 3 h and increased again by 6 h after nicotine. Daily administration of nicotine for 14 days increased Met-Enk content and PPE mRNA in the striatum of mice as well. Taken together, our results suggest that nicotinic receptors modulate Met-Enk content and PPE mRNA in the mouse striatum.

Animals↗

PubMed1994

Inhibition of morphine tolerance and dependence by diazepam and its relation to the CNS Met-enkephalin levels.

The effect of diazepam on the development of morphine tolerance and dependence was investigated. Male Sprague-Dawley rats were rendered tolerant and dependent by subcutaneous implantation of six morphine pellets. Diazepam (0.025, 0.25 or 2.5 mg/kg body weight) was once daily injected intraperitoneally into rats starting on the first day of implantation. Antinociception was measured by tail-flick (TF) and hot plate (HP) tests, and the extent of sedation determined by a rotarod test before and one hour after diazepam injections everyday for 5 days. Physical dependence on morphine was assessed by an antagonist-precipitated abstinence syndrome on the fifth day of treatment by injecting naloxone 10 mg/kg subcutaneously. Diazepam (0.025-2.5 mg/kg body weight) did not produce significant antinociception or sedation (sensorimotor impairment) in rats implanted with placebo pellets. Diazepam (0.25 and 2.5 mg/kg) inhibited tolerance to TF antinociception in rats implanted with morphine pellets. Sedation as evidenced by sensorimotor impairment induced by morphine pellet implantation was not influenced by diazepam (0.025-2.5 mg/kg). Diazepam administration (0.25 mg/kg) also decreased the degree of jumping behavior observed following naloxone injection in morphine pellet implanted rats. Serum morphine concentration in morphine-diazepam treated rats was not significantly different from that in morphine-saline treated rats. Finally, a decrease in the Met-enkephalin levels observed in the hypothalamus, hippocampus, cortex and spinal cord of morphine dependent rats was reversed by injecting diazepam along with morphine pellet implantation. These results suggest that diazepam inhibits morphine tolerance and dependence, and also prevents morphine-induced decrease in the CNS Met-enkephalin levels in morphine dependent rats.

Animals↗

PubMed1994

Plasma nicotine, plasma beta-endorphin and mood states during periods of chronic smoking, abstinence and nicotine replacement.

Nicotine is known to release neuroendocrine substances which may subsequently reinforce smoking behavior by improving mood states. The purpose of this study was to examine changes in plasma beta-endorphin and mood states during periods of chronic smoking, abstinence from smoking, and abstinence while chewing nicotine gum. A modified A-B-A-C design was used. Normal male volunteers were randomly assigned to an experimental or control group. Over a 12-day protocol, experimental subjects smoked ad libitum for 2 days, were abstinent for 4 days, resumed smoking for 2 days, and then chewed nicotine gum for the final 4 days. Control subjects smoked ad libitum throughout the entire protocol. Results indicated that changes in plasma beta-endorphin levels were not related to changes in the four smoking conditions. Plasma nicotine and mood states were related, such that dysphoric moods increased during abstinence from smoking in comparison to the control group. To investigate further the relationships between nicotine, beta-endorphin and reinforcement for smoking, it may be necessary to characterize endogenous opioid peptide release in the central nervous system during smoking.

Adult↗

PubMed1994

Sodium ions modulate differentially the effect of a benzodiazepine agonist on rat spinal mu-, delta- and kappa-opioid receptors.

Midazolam, a benzodiazepine receptor agonist, when injected intrathecally either enhances or decreases antinociception produced by intrathecal administration of morphine in rats. Furthermore, midazolam inhibits binding of several opioid ligands to spinal opioid receptors in vitro [Rattan et al, Anesth Analg 1991;73:124-131]. This study was designed to investigate the effect of midazolam on binding of mu-, delta- and kappa-ligands to rat spinal opioid receptors in the presence of sodium ions which differentially modulate binding of opioid agonists and antagonists. Sodium ions (50-1,000 mmol/l) selectively increased the specific binding of [3H]naloxone but decreased binding of opioid agonists such as [3H]DAGO (Tyr-D-Ala-Gly-Methyl-Phe-Gly-ol-enkephalin) to mu-receptors, [3H]DSTLE (Tyr-D-Ser-Gly-Phe-Leu-Thr-enkephalin) to delta-receptors and [3H]EKC (ethylketocyclazocine) to kappa-receptors in rat spinal cord in vitro. Midazolam (1-100 mumol/l) inhibited the binding of [3H]naloxone, [3H]DAGO, [3H]DSTLE and [3H]EKC. Sodium ions (100 mmol/l) antagonized the inhibition of binding of [3H]naloxone and [3H]DSTLE by midazolam by increasing IC50 values for midazolam. However, sodium ions potentiated the inhibition of binding of [3H]DAGO by midazolam by decreasing IC50 value for midazolam and had a mixed effect on binding of [3H]EKC in the presence of midazolam. Scatchard analysis performed in the presence of sodium ions and/or midazolam confirmed the specific effects of sodium ions as well as midazolam on the Bmax and KD of mu-, delta-, and kappa-receptors. These results suggest for the first time that sodium ions play an important role in the modulation of spinal opioid receptors by benzodiazepines. Sodium ions potentiate the inhibition of DAGO binding but antagonize the inhibition of naloxone and DSTLE binding by midazolam in rat spinal cord.

Animals↗

PubMed1994

Methionine-enkephalin concentrations in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of U-50,488H-tolerant and abstinent rats.

Effects were determined of chronic administration and withdrawal of a highly selective kappa-opioid receptor agonist, U-50,488H, on methionine-enkephalin levels in central and peripheral tissues of male Sprague-Dawley rats. Rats were rendered tolerant to and physically dependent on U-50,488H by twice daily injections of 25 mg/kg of this compound for 5 days. Rats deemed abstinent were injected with this drug for 4 days and sacrificed on 5th day. Methionine-enkephalin concentration increased in the hippocampus of U-50,488H-tolerant-dependent rats, whereas in abstinent rats, its level was elevated only in the hypothalamus. Levels of methionine-enkephalin in the pituitary gland of U-50,488H-tolerant-dependent or abstinent rats were unchanged. Among peripheral tissues, methionine-enkephalin concentration decreased in the adrenal gland of U-50,488H-tolerant-dependent rats. In the U-50,488H-abstinent rats, methionine-enkephalin concentration was elevated in the heart. In tissues of morphine- and U-50,488H-tolerant-dependent and abstinent rats methionine-enkephalin concentrations were affected differentially, suggesting inherent differences in mu- and kappa-opiate-mediated tolerance-dependence and abstinence processes.

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

PubMed1994

beta-Endorphin-like immunoreactivity in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of U-50,488H-tolerant and -abstinent rats.

The effect was determined of trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzene- acetamide methane sulfonate (U-50,488H), a kappa opioid agonist, -induced tolerance dependence and abstinence on the levels of beta-endorphin in discrete brain regions, spinal cord, pituitary gland, plasma and peripheral tissues of male Sprague-Dawley rats. The brain regions examined were hypothalamus, hippocampus, amygdala, midbrain, corpus striatum, pons-medulla and cortex. The peripheral tissues included kidneys, spleen, adrenals and heart. Rats were made tolerant dependent on U-50,488H by intraperitoneal injections of the drug (25 mg/kg) twice a day for 4 days. Vehicle-injected rats served as controls. Rats that were labeled as tolerant dependent were injected with U-50,488H (25 mg/kg) on day 5 and killed 1 hr later, whereas those labeled as abstinent were killed without injection of the drug. Rats serving as controls were injected with the vehicle. Tolerance to the analgesic and hypothermic effects of U-50,488H developed, as evidenced by a decrease in the intensity of responses in chronic U-50,488H-treated compared with chronic vehicle-treated rats. In U-50,488H-tolerant rats, the concentration of beta-endorphin was increased in hippocampus, corpus striatum, pituitary gland, plasma, kidneys and adrenals compared with vehicle-injected controls. In U-50,488H-abstinent rats, the concentration of beta-endorphin was increased in pons-medulla and amygdala, whereas the concentration of beta-endorphin did not change in the pituitary gland, plasma and peripheral tissues. In general, chronic treatment with a kappa opioid agonist results in increases in the concentration of beta-endorphin in specific tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1993

The effect of U-50,488H tolerance-dependence and abstinence on the levels of dynorphin (1-13) in brain regions, spinal cord, pituitary gland and peripheral tissues of the rat.

Male Sprague-Dawley rats were rendered tolerant to and physically dependent on U-50,488H, a kappa-opiate agonist, by injecting 25 mg/kg of the drug intraperitoneally twice a day for 4 days. Two sets of rats were used. Rats labeled as tolerant-dependent were injected with U-50,488H (25 mg/kg) 1 h before sacrificing on day 5, whereas the abstinent rats were sacrificed on day 5 without the injection of U-50,488H. Of all the tissues on day 5 without the injection of U-50,488H. Of all the tissues examined, the pituitary gland had the highest level of dynorphin (1-13), whereas the heart had the lowest level. The levels of dynorphin (1-13) increased in the hypothalamus, hippocampus and pons/medulla of U-50,488H tolerant-dependent rats, whereas in abstinent rats the levels of dynorphin (1-13) were elevated only in the midbrain. The levels of dynorphin (1-13) in the pituitary gland of U-50,488H tolerant-dependent or abstinent rats were unchanged. In peripheral tissues, the levels of dynorphin (1-13) in the heart of U-50,488H tolerant-dependent rats were increased. In the abstinent rats they were elevated in the adrenals, spleen, and the heart but were decreased in the kidneys. Compared to morphine tolerant-dependent and abstinent rats, significant differences in the levels of dynorphin (1-13) in tissues of 50,488H tolerant-dependent and abstinent rats were observed and may explain many pharmacological differences in the mu- and kappa-opiate induced tolerance-dependence and abstinence processes.

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

PubMed1993

Inhibition of morphine-induced tolerance and dependence by a benzodiazepine receptor agonist midazolam in the rat.

We investigated whether midazolam administration influenced morphine-induced antinociception and tolerance and dependence in the rat. Antinociception was assessed by the tail-flick (TF) and the hot-plate test (HP 52 degrees C). Morphine tolerance developed after daily single injections of morphine for 11 days. The effect of midazolam on morphine-induced antinociception and tolerance was assessed by giving daily injections of various doses of midazolam for 11 days. The first injection of saline or midazolam was given intraperitoneally and 30 min later morphine (10 mg/kg body weight) was administered subcutaneously. Antinociception was monitored by measuring TF and HP latencies 60 min after the second injection. Midazolam was injected at four different concentrations: 0.03, 0.1, 0.3, and 3 mg/kg body weight. Chronic administration of morphine resulted in the development of tolerance to antinociception in both TF and HP tests, with rats exhibiting baseline antinociception on Day 9. Animals treated with midazolam alone showed little antinociception on Days 3-9. However, midazolam administration in morphine-treated animals attenuated morphine-induced tolerance to antinociception on Days 1-11 as measured by the tail-flick test. Midazolam also decreased the jumping behavior following naloxone injections in morphine-dependent rats. These results suggest that midazolam may prolong the effects of morphine by delaying morphine-induced development of tolerance to antinociception. Midazolam also attenuated a decrease in weight gain induced by chronic injections of morphine.

Animals↗