dynorphins and Morphine-Dependence

To investigate the effect of processed Aconiti tuber (PAT) administered during or after the time of conditioned place preference (CPP) training on the extinction and reinstatement of morphine-priming CPP in rats. The dynorphin level in rats' nucleus accumbens (NAc) is detected as a target of the Dynorphin/Kappa Opioid Receptor (KOR) system for the possible mechanism.. Eight groups of rats were subcutaneously (s.c.) injected with morphine (10mg/kg) (on days 2,4,6,8) or saline (1ml/kg) (on days 3,5,7,9) alternately for 8 days. Five groups, including groups (Mor + Water, Mor + PAT (1.0/3.0g/kg) (S) and Sal + PAT(1.0/3.0g/kg)), were orally given distilled water or PAT 1.0 or 3.0 g/kg daily on days 1-8 during CPP training while other three groups, including groups (Sal + Water and Mor + PAT (1.0/3.0g/kg)(P), were given distilled water or PAT daily from day 10 until CPP was extinct. Morphine 1mg/kg (s.c.) was used to reinstate the extinct CPP and the CPP scores were recorded. The dynorphin concentration in nucleus accumbens (NAc) was assayed by radioimmunoassay after the last CPP measurement.. 1) The CPP extinction shortened in Mor + PAT (1.0/3.0 g/kg) (S) groups but extended in Mor + PAT (1.0/3.0 g/kg)(P) groups. 2) Morphine-priming CPP did not change either in Mor + PAT (1.0/3.0 g/kg) (S) or Mor + PAT (1.0/3.0 g/kg)(P) groups. 3) The dynorphin concentration in NAc increased either in Mor + PAT (1.0/3.0 g/kg)(S) or Mor + PAT (1.0/3.0 g/kg)(P) groups.. 1) PAT shortened the extinction from morphine induced CPP when administrated before CPP acquisition, whereas it extended the extinction when administrated after CPP formation. 2) PAT administrated during or after CPP training did not affect morphine-priming reinstatement of morphine induced CPP. 3) Dynorphin/KOR system might be a target to regulate morphine-induced CPP extinction but not reinstatement.

Topics: Aconitum; Analgesics, Opioid; Animals; Behavior, Animal; Conditioning, Psychological; Dynorphins; Extinction, Psychological; Male; Morphine; Morphine Dependence; Nucleus Accumbens; Plant Extracts; Plant Tubers; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Signal Transduction

Much data suggest that the binding of dynorphin-like peptides to kappa-opioid receptors (KORs) during the administration of and withdrawal from a variety of addictive drugs is aversive and serves to limit the reinforcing properties of those drugs and to enhance tolerance, withdrawal, and the probability of stress-induced relapse. In this study, we examined the role of KORs in mediating opioid withdrawal and its aversive consequences in rats. We found that selective blockade of KORs by i.p. administration of 20mg/kg nor-binaltorphimine (nor-BNI) 5h prior to naltrexone-precipitated withdrawal in morphine-dependent rats decreased feces excreted during a 30-min withdrawal session. More critically, this injection of nor-BNI decreased the subsequent conditioned place aversion (CPA) for the withdrawal chamber 2 days later. The subsequent finding that administration of nor-BNI 2h following withdrawal did not affect the CPA 2 days later suggested that nor-BNI reduced the CPA in the prior experiment because it reduced the aversive effects of withdrawal, not because it reduced the aversive/anxiogenic effects of the withdrawal chamber at the time of CPA testing. These data indicate that the binding of dynorphin-like peptides to KORs during opioid withdrawal serves to enhance withdrawal and its aversive consequences and suggest that selective KOR antagonists may be useful in reducing these aversive effects and consequent relapse.

Topics: Animals; Conditioning, Psychological; Defecation; Dynorphins; Male; Morphine; Morphine Dependence; Motor Activity; Naltrexone; Narcotic Antagonists; Narcotics; Neurotransmitter Agents; Random Allocation; Rats, Long-Evans; Receptors, Opioid, kappa; Spatial Behavior; Substance Withdrawal Syndrome

Our previous studies indicated that processed Aconiti tuber (PAT), a traditional Chinese herbal medicine, had antinociceptive effects and inhibitory effects on morphine tolerance by activation of kappa-opioid receptor (KOR). Preclinical studies also demonstrated that KOR agonists functionally attenuate addictive behaviors of morphine, such as conditioned place preference (CPP). Therefore, we hypothesize that PAT may inhibit morphine-induced CPP in rats.. (1) Five groups of rats (n=8 for each group) were alternately subcutaneous (s.c.) injected with morphine 10mg/kg (one group receive normal saline as a control) and normal saline for 8 days and oral co-administrated with distilled water or PAT 0.3, 1.0, or 3.0 g/kg daily on days 2-9 during CPP training, respectively. (2) Other four groups of rats were randomly s.c. injected with nor-binaltorphimine (nor-BNI; 5mg/kg) or normal saline (as a control) 120 min before alternately s.c. with morphine and normal saline and oral co-administrated with distilled water or PAT 3.0 g/kg daily. Each rat was acquired pre-conditioning and post-conditioning CPP data and assayed dynorphin concentrations by radioimmunoassay in rat's nucleus accumbens (NAc) after CPP training.. (1) PAT 1.0 or 3.0 g/kg dose-dependently decreased the morphine-induced increase of CPP scores. (2) Nor-BNI completely antagonized the inhibition of PAT on morphine-induced CPP. (3) PAT dose-dependently increased dynorphin content in rats' NAc after CPP training.. (1) PAT dose-dependently inhibited morphine-induced CPP. (2) The inhibition of PAT on morphine-induced CPP was probably due to activation of KOR by increasing dynorphin release in rats' NAc.

Topics: Aconitum; Animals; Behavior, Addictive; Behavior, Animal; Conditioning, Operant; Dose-Response Relationship, Drug; Drug Tolerance; Drugs, Chinese Herbal; Dynorphins; Male; Morphine Dependence; Naltrexone; Narcotic Antagonists; Nucleus Accumbens; Phytotherapy; Plant Tubers; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa

The effects of various protease inhibitors on naloxone-precipitated withdrawal jumping were examined in morphine-dependent mice. The doses of morphine were subcutaneously given twice daily for 2 days (day 1, 30 mg/kg; day 2, 60 mg/kg). On day 3, naloxone (8 mg/kg) was intraperitoneally administered 3h after final injection of morphine (60 mg/kg), and the number of jumping was immediately recorded for 20 min. Naloxone-precipitated withdrawal jumping was significantly suppressed by the intracerebroventricular administration of N-ethylmaleimide (0.5 nmol) and Boc-Tyr-Gly-NHO-Bz (0.4 nmol), inhibitors of cysteine proteases involved in dynorphin degradation, 5 min before each morphine treatment during the induction phase, with none given on the test day, as well as by dynorphin A (62.5 pmol) and dynorphin B (250 pmol). However, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, caused no changes. The present results suggest that cysteine protease inhibitors suppress naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of dynorphin degradation.

Topics: Animals; Cysteine Proteinase Inhibitors; Dipeptides; Dynorphins; Ethylmaleimide; Injections, Intraventricular; Male; Mice; Morphine Dependence; Naloxone; Substance Withdrawal Syndrome

Several groups maintain that morphine tolerance and dependence correlate with increased activity of protein kinases ERK1/2 and P38 MAPK and PKC as well as elevated levels of the neuropeptides dynorphin (DYN), substance P (sP), and calcitonin gene-related peptide (CGRP) in spinal cord dorsal horn (SCDH). They demonstrate that tolerance and dependence can be prevented, and sometimes reversed, by constitutive genetic deletion or pharmacological inhibition of these factors. Recently, we showed that mice with a constitutive deletion of the GluR5 subunit of kainate receptors (GluR5 KO) are not different from wild type (WT) littermates with respect to baseline nociceptive thresholds as well as acute morphine antinociception, morphine physical dependence and conditioned place preference. However, unlike WT, GluR5 KO mice do not develop antinociceptive tolerance following systemic morphine administration. In this report, we examined levels of these mediators in SCDH of WT and GluR5 KO mice following subcutaneous implantation of placebo or morphine pellets. Surprisingly, spinal DYN and CGRP, along with phosphorylated ERK2 (pERK2), P38 (pP38) and PKCgamma (pPKCgamma) are elevated by deletion of GluR5. Additionally, chronic systemic morphine administration increased spinal pERK2, pP38 and pPKCgamma levels in both tolerant WT and non-tolerant GluR5 KO mice. In contrast, while morphine increased spinal DYN and CGRP in WT mice, DYN remained unchanged and CGRP was reduced in GluR5 KO mice. These observations suggest that spinal ERK2, P38 and PKCgamma are likely involved in multiple adaptive responses following systemic morphine administration, whereas DYN and CGRP may contribute selectively to the development of antinociceptive tolerance.

Topics: Animals; Calcitonin Gene-Related Peptide; Drug Implants; Drug Tolerance; Dynorphins; Enzyme Activation; Enzyme Induction; Exploratory Behavior; Male; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Morphine; Morphine Dependence; Narcotics; p38 Mitogen-Activated Protein Kinases; Pain; Pain Threshold; Phosphorylation; Posterior Horn Cells; Protein Kinase C; Protein Processing, Post-Translational; Receptors, Kainic Acid

The transcription factor DeltaFosB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FosB/DeltaFosB expression in both hypothalamic and extrahypothalamic brain stress system during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FosB/DeltaFosB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain stress system in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FosB/DeltaFosB in CRF-, TH- and DYN-positive neurons. FosB/DeltaFosB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A(2) noradrenergic part of the nucleus tractus solitarius (NTS-A(2)). Morphine dependence and withdrawal evoked an increase in FosB/DeltaFosB-TH and FosB/DeltaFosB-CRF double labelling in NTS-A(2) and PVN, respectively, besides an increase in TH levels in NTS-A(2) and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FosB/DeltaFosB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain stress system, which have been proposed to be directly related to addiction.

Topics: Animals; Brain; Corticotropin-Releasing Hormone; Dynorphins; Enkephalins; Hypothalamo-Hypophyseal System; Male; Morphine; Morphine Dependence; Pituitary-Adrenal System; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Stress, Physiological; Substance Withdrawal Syndrome; Tyrosine 3-Monooxygenase

Modulatory actions on morphine-induced effects, such as tolerance and withdrawal, have been noted for dynorphin A(1-13) [Dyn A(1-13)] and similar peptides. These are currently of limited therapeutic potential due to extensive metabolism by human metabolic enzymes resulting in a half-life of less than 1 min in human plasma. The purpose of this study was to identify stabilized dynorphin A (Dyn A) derivatives, to determine their metabolic routes in human plasma, and to assess whether the pharmacodynamic activity is retained.. The stability of peptides in human plasma was tested using in vitro metabolism studies with and without enzyme inhibitors. Identification of the generated metabolites was performed by mass spectrometry after high performance liquid chromatography (HPLC) separation. The in vivo activity of a stabilized dynorphin was tested by tail-flick assay in morphine-tolerant rats.. Though amidation of the Dyn A(1-13) was able to stop the majority of C-terminal degradation, metabolism of Dyn A(1-10) amide continued by captopril sensitive enzymes, suggesting that Dyn A(1-13) amide is a better candidate for additional stabilization. Two Dyn A(1-13) amide derivatives further stabilized at the N-terminal end, [D-Tyr1]-Dyn A(1-13) amide and [N-Met-Tyr1]-Dyn A(1-13) amide, showed half-lives in plasma of 70 and 130 min, respectively. The most stable derivative [N-Met-Tyr1]-Dyn A(1-13) amide was tested successfully for retention of the pharmacological activity in modulating antinociceptive activity.. [N-Met-Tyr1]-Dyn A(1-13) amide showed significant stability and antinociceptive activity in the tail-flick test, thus pointing to the clinical potential of this derivative in the management of pain as well as its potential activity in suppressing opiate tolerance and withdrawal.

Topics: Aminopeptidases; Analgesics; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Carboxypeptidases; Drug Stability; Drug Tolerance; Dynorphins; Enzyme Inhibitors; Half-Life; Leucine; Male; Morphine Dependence; Pain Measurement; Rats; Rats, Sprague-Dawley; Succinates; Sulfhydryl Compounds

To investigate the involvement of immunoreactive-dynorphin A in the inhibitory effect of N-nitro-L-arginine on the morphine physical dependence in rats.. The rats were rendered dependent on morphine by subcutaneous administration of morphine solution three times daily in a manner of dose increment of 5 mg.kg(-1) for 6 days. The degree of morphine physical dependence was monitored by scoring the abstinence syndromes precipitated by 5 mg.kg(-1) naloxone of the rats. The expression levels of immunoreactive dynorphin A in tissues were determined using a radioimmunoassay.. Intraperitoneal injection of 5 mg.kg(-1) N-nitro-L-arginine suppresses most of the withdrawal symptoms of morphine dependent rats. N-nitro-L-arginine can elevate the expression of immunoreactive dynorphin.. Chronic N-nitro-L-arginine administration can inhibit the development of morphine physical dependence in a manner of dose-dependence, which is significantly related to its role of regulating the endogeneous dynorphin system.

Topics: Animals; Dose-Response Relationship, Drug; Dynorphins; Male; Morphine Dependence; Nitroarginine; Rats; Rats, Sprague-Dawley

To study the relationship between the levels of immunoreactive dynorphin A1-13 (ir-dynorphin A1-13) and the degree of morphine dependence.. The levels of ir-dynorphin A1-13 in discrete brain regions, spinal cord, and plasma in rats were determined by radioimmunoassay, and the degree of morphine dependence was assessed by scoring withdrawal signs on d 3, d 6, and d 12.. Morphine injection s.c. decreased the levels of ir-dynorphin A1-13 in spinal cord, pituitary, and plasma. The levels of ir-dynorphin A1-13 in hippocampus and hypothalamus were increased. No changes in cortex, midbrain, cerebellum, pons, and medulla were observed. With continuous injection of morphine, withdrawal signs scores were increased on d 6, but there was no difference between the scores of d 6 and d 12.. The changes of the levels of endogenous ir-dynorphin A1-13 in pituitary, spinal cord, and plasma were compatible with the degree of morphine dependence.

Topics: Animals; Dynorphins; Male; Morphine Dependence; Peptide Fragments; Pituitary Gland; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance Withdrawal Syndrome

The secretion of oxytocin (OXT) from the neurohypophysis is modulated by the actions of opioids acting via kappa-receptors. The vasopressin (AVP)-containing nerve terminals in the neurohypophysis contain the kappa-opioid agonist dynorphin, but endogenous opioid restraint of OXT secretion is observed even when AVP release is not activated, suggesting that another source of opioids is responsible for modulating OXT secretion. We now report that acute stimulation of the rat neural lobe in vivo results in depletion of the neural lobe content of OXT, AVP, dynorphin A1-17, dynorphin A1-8 and metenkephalin (Met-Enk). The dynorphin content is depleted to a similar extent as that of OXT and AVP; a correlation analysis suggests that while most dynorphin is co-secreted with AVP, a significant portion is co-secreted with OXT, consistent with a co-localisation of dynorphin with OXT. Met-Enk was depleted to a lesser extent than either hormone, consistent with a partial localisation in non-releasable pools. However, depletion of Met-Enk was also observed following naloxone-precipitated opioid withdrawal accompanying selective hypersecretion of OXT, suggesting co-secretion of OXT and Met-Enk. Met-Enk is a mu-opioid receptor agonist, but extended forms of Met-Enk, as we now report, are active at neurohypophysial kappa-receptors.

Topics: Animals; Arginine Vasopressin; Cytoplasmic Granules; Dynorphins; Electric Stimulation; Enkephalin, Methionine; Female; Male; Morphine; Morphine Dependence; Naloxone; Organ Culture Techniques; Oxytocin; Pituitary Gland, Posterior; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Opioid, kappa; Receptors, Opioid, mu

Previously, we demonstrated that the expression of opiate withdrawal and antinociceptive tolerance can be suppressed by dynorphin (dyn) A-(1-13) in morphine-dependent mice. In this study, it was shown that the normal, endogenous dyn, dyn A-(1-17) also possessed this suppressive property. While using the nonopioid dyn analog, [des-Tyr1]dyn A [dyn A-(2-17)] as a negative control, we discovered unexpectedly that this peptide fragment also suppressed naloxone-induced withdrawal and the expression of morphine tolerance in morphine-dependent mice. Thus, an extensive structure activity relationship was studied using 11 peptide fragments. It was determined that the amino acid sequence of dyn A was required for the suppressive activity because dyn B and alpha-neoendorphin both failed to suppress naloxone-precipitated withdrawal jumping. Of the [des-Tyr1]dyn fragments, the minimal amino acid sequence required to suppress naloxone-induced withdrawal was determined to be dyn A-(2-8), containing the sequence G-G-F-L-R-R-I.

Topics: Amino Acid Sequence; Animals; Drug Tolerance; Dynorphins; Male; Mice; Molecular Sequence Data; Morphine; Morphine Dependence; Naloxone; Nociceptors; Peptide Fragments; Structure-Activity Relationship; Substance Withdrawal Syndrome

The effect of morphine tolerance dependence and protracted abstinence on the levels of dynorphin (1-13) in discrete brain regions, spinal cord, pituitary gland and peripheral tissues was determined in male Sprague-Dawley rats. Of all the tissues examined, the highest level of dynorphin (1-13) was found to be in the pituitary gland. Among the brain regions and spinal cord examined, the levels of dynorphin (1-13) in descending order were: hypothalamus, spinal cord, midbrain, pons and medulla, hippocampus, cortex, amygdala and striatum. The descending order for the levels of dynorphin (1-13) in peripheral tissues was: adrenals, heart and kidneys. In morphine tolerant rats, the levels of dynorphin (1-13) increased in amygdala but were decreased in pons and medulla. In morphine abstinent rats, the levels of dynorphin (1-13) were increased in amygdala, hypothalamus and hippocampus. The levels of dynorphin (1-13) were increased in pituitary but decreased in spinal cord and remained so even during protracted abstinence. The levels of dynorphin (1-13) in the peripheral tissues of morphine tolerant rats were unaffected. However, in the heart and kidneys of morphine abstinent rats, the levels of dynorphin (1-13) were increased significantly. It is concluded that both morphine tolerance and abstinence modify the levels of dynorphin (1-13) in pituitary, central and peripheral tissues. Morphine abstinence differed from non-abstinence process in that there were additional changes (increases) in the levels of dynorphin (1-13) in brain regions (hypothalamus and hippocampus) and peripheral tissues (heart and kidneys) and may contribute to the symptoms of the morphine abstinence syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Glands; Analgesics; Animals; Brain Chemistry; Drug Tolerance; Dynorphins; Heart; Kidney; Male; Morphine; Morphine Dependence; Myocardium; Peptide Fragments; Pituitary Gland; Rats; Rats, Inbred Strains; Spinal Cord; Substance Withdrawal Syndrome

Chronic exposure of receptors to antagonists generally results in upregulation and/or supersensitivity. On the other hand, the noncompetitive NMDA receptor antagonists ketamine (K) and dextromethorphan (DM) suppress opiate abstinence syndrome by blocking NMDA receptors. Therefore, 40 mg/kg ketamine (K), 5 mg/kg dextromethorphan (DM), 5 mg/kg morphine (M) and 2 mg/kg naloxone (NL) alone or in combination with NL were IP administered to the rats five times during the daytime only for five days to see whether they would intensify abstinence syndrome through upregulation and/or supersensitivity of NMDA receptors. Three days following the implantation of three M-containing pellets, abstinence syndrome was brought about by 2 mg/kg NL injection. Jumping, wet dog shake, writhing, teeth chattering, diarrhoea, defecation and ptosis were observed for ten min. All drugs used alone or in combination with NL increased the intensity of abstinence syndrome. Since K and DM are noncompetitive NMDA receptor antagonists, the intensifying effect of NL or M was considered to be related to their interactions with NMDA receptors. Furthermore, on the basis of the results of the previous and present study, NL was claimed to act on NMDA receptors, like other opioids, but with higher affinity for and weaker blocking effect on NMDA receptors.

Topics: Amino Acids; Analgesics; Animals; Behavior, Animal; Dextromethorphan; Dynorphins; Injections, Spinal; Kainic Acid; Male; Morphine Dependence; Naloxone; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Substance Withdrawal Syndrome

Rats were rendered dependent on morphine by repeated injections of morphine, in increasing doses for 14 days and sacrificed. Levels of peptides in the dorsal spinal cord and dorsal root ganglia were analyzed in rats decapitated 2 hr, 24 hr (acute abstinent) or 7 days (late abstinent) respectively, after the last injection of drug. Dynorphin A was significantly decreased in rats abstinent for 24 hr, while dynorphin B remained unaffected. Substance P and CGRP, both putative transmitters in nociceptive primary afferent neurones, and partly existing together in the same neurone, were affected differently. Significantly less substance P but unchanged levels of CGRP were detected in rats abstinent for 24 hr, while on the other hand, CGRP but not levels of substance P, were increased 2 hr after the final injection. In dorsal root ganglia, levels of substance P were lower at 2 hr, while levels of CGRP were unaffected. In late (7 days) abstinence, no effect of opiate on any peptide was detected.

Topics: Animals; Calcitonin Gene-Related Peptide; Dynorphins; Endorphins; Male; Morphine; Morphine Dependence; Radioimmunoassay; Rats; Rats, Inbred Strains; Spinal Cord; Substance P; Time Factors

Many investigations have suggested that endogenous opioids are involved in the regulation of food ingestion. Pharmacological studies have clearly demonstrated that kappa opioid receptors play a role in the modulation of feeding. Dynorphin, a peptide which appears to be the endogenous ligand of the kappa receptor, is a potent stimulator of feeding and its levels in the central nervous system are altered under conditions associated with alterations in the feeding drive. The enhancement of feeding produced by dynorphin involves both the opioid and non-opioid portion of the molecule. These studies suggest that dynorphin is an endogenous stimulator of feeding.

Topics: Animals; Appetite; Dynorphins; Eating; Endorphins; Morphine Dependence; Rats; Receptors, Opioid; Species Specificity; Structure-Activity Relationship

Adult female Sprague-Dawley rats were prepared with permanent cortical EEG and temporalis EMG electrodes and i.v. cannulae. They were made tolerant to and physically dependent on morphine by automatic, hourly injections. These physically dependent rats were then trained to lever press for 10 mg/kg injections of morphine on a fixed ratio (FR) schedule of reinforcement. Upon stabilization of morphine self-administration at a FR-10, dynorphin-[1-13] (DYN) or D-ala2-dynorphin-[1-11] (D-ala2-DYN) at doses of 125 or 250 micrograms/kg/inj was substituted for morphine. Rats self-administered these opioid-like peptides at both dose levels. As expected, self-injections were more numerous at the lower dose. No signs of morphine withdrawal were seen during the peptide substitutions. Following DYN or D-ala2-DYN abstinence, no withdrawal symptoms were noted. The question is raised as to whether DYN or D-ala2-DYN and morphine are producing their reinforcing effects in sustaining self-administration via the same receptor populations. Since morphine abstinence is associated with severe withdrawal symptoms and the peptides studied are not, the involvement of separate receptor populations in the process of dependence on morphine and these opioid-like peptides is indicated. In conclusion, both a mu and two kappa agonists exhibited an analogous reinforcing property in the rat. However, the degree of physical dependence and the intensity of withdrawal differed; being higher with the mu agonist and lower with the kappa agonists.

Topics: Animals; Dynorphins; Electroencephalography; Endorphins; Female; Humans; Morphine Dependence; Narcotics; Peptide Fragments; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, mu; Self Administration

Topics: Animals; Brain; Dynorphins; Endorphins; Female; Humans; Morphine Dependence; Pituitary Gland; Radioimmunoassay; Rats; Rats, Inbred Strains

Topics: Animals; Behavior, Animal; Drug Tolerance; Dynorphins; Endorphins; Humans; Macaca mulatta; Morphine Dependence; Peptide Fragments

In previous studies, we observed that dynorphin- (1-13), but not dynorphin-(1-9), can significantly inhibit morphine- or beta-endorphin-induced analgesia despite not having any appreciable analgesic activity itself. Dynorphin-(1-13) showed no inhibitory effect on Sandoz FK33824-induced analgesia. In the present study, we examined the effect of dynorphin on morphine-, beta-endorphin-, D-ala2-D-leu5-enkephalin- or Sandoz FK33824-induced analgesia in both naive, morphine-tolerant and morphine-dependent mice. It was found that although dynorphin may inhibit morphine- or beta-endorphin-induced analgesia in naive animals, the peptide is not effective in inhibiting D-ala2-D-leu5-enkephalin- or Sandoz FK33824-induced analgesia. Dynorphin is also effective in blocking spontaneous withdrawal jumping in morphine-dependent animals. It is suggested that dynorphin-(1-13) may play a modulatory role in regulating analgesia due to morphine or beta-endorphin, but not that due to enkephalin. The action of peptides on morphine- or beta-endorphin-induced analgesia in the naive state is different from that of the tolerant state, suggesting that dynorphin may be involved in the development of morphine tolerance and physical dependence.

Topics: Analgesics; Animals; beta-Endorphin; Drug Interactions; Drug Tolerance; Dynorphins; Endorphins; Enkephalins; Humans; Male; Mice; Mice, Inbred ICR; Morphine; Morphine Dependence; Substance Withdrawal Syndrome