Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We compared the physical dependence liability of biphalin, a dimeric enkephalin analogue that possesses high antinociceptive activity, with that of morphine in equipotent intravenous doses. Naloxone challenge produced severe withdrawal signs after a 5-day infusion of morphine but only minor withdrawal signs after a 5-day biphalin infusion. In a cross-dependence study, biphalin did not suppress body weight loss after morphine withdrawal, but successfully suppressed weight loss after pentazocine withdrawal. These data support consideration of biphalin as a new analgesic with a novel pharmacological profile and minimum dependence liability.
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PMID:The opioid peptide analogue biphalin induces less physical dependence than morphine. 1150 44

Cholestasis is associated with elevated plasma level of endogenous opioid peptides. Naloxone-precipitated withdrawal syndrome has been described in a mouse model of acute cholestasis. Thus we aimed at determining whether central noradrenergic hyperactivity is involved in manifestation of naloxone-precipitated withdrawal syndrome in mice with obstructive cholestasis. Acute cholestasis was induced by bile duct resection in mice and physical dependence was observed by precipitating a withdrawal syndrome with naloxone (2 mg/kg, intraperitoneally) 5 days after induction of cholestasis. Administration of clonidine (0.1 mg/kg, intraperitoneally), an alpha2-adrenoceptor agonist, 15 min. before naloxone injection significantly alleviates withdrawal severity in cholestatic mice. However, pretreatment of animals with yohimbine (3 mg/kg, intraperitoneally), an alpha2-adrenoceptor antagonist, 15 min. before clonidine blocked this ameliorative effect of clonidine. The results of this study support the evidence for involvement of the alpha2-adrenoceptors in the withdrawal syndrome of cholestasis in a mouse model.
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PMID:Clonidine attenuates naloxone-induced opioid-withdrawal syndrome in cholestatic mice. 1158 83

This study examined the role of spinal calcitonin gene-related peptide (CGRP), substance P, and prostaglandins in the development and expression of opioid physical dependence. Administration of escalating doses (5 - 100 mg kg-1, i.p.) of morphine for 7 days markedly elevated CGRP and substance P- immunoreactivity in the dorsal horn of the rat spinal cord. Naloxone (2 mg kg-1, i.p.) challenge decreased both CGRP and substance P immunoreactivity and precipitated a robust withdrawal syndrome. Acute intrathecal pre-treatment with a CGRP receptor antagonist, CGRP(8 - 37) (4, 8 microg), a substance P receptor antagonist, SR 140333 (1.4, 2.8 microg), a cyclo-oxygenase (COX) inhibitor, ketorolac (30, 45 microg), and COX-2 selective inhibitors, DuP 697 (10, 30 microg) and nimesulide (30 microg), 30 min before naloxone challenge, partially attenuated the symptoms of morphine withdrawal. CGRP(8 - 37) (8 microg), but no other agents, inhibited the decrease in CGRP immunoreactivity. Chronic intrathecal treatment with CGRP(8 - 37) (4, 8 microg), SR 140333 (1.4 microg), ketorolac (15, 30 microg), DuP 697 (10, 30micro g), and nimesulide (30 microg), delivered with daily morphine injection significantly attenuated both the symptoms of withdrawal and the decrease in CGRP but not substance P immunoreactivity. The results of this study suggest that activation of CGRP and substance P receptors, at the spinal level, contributes to the induction and expression of opioid physical dependence and that this activity may be partially expressed through the intermediary actions of prostaglandins.
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PMID:The role of spinal neuropeptides and prostaglandins in opioid physical dependence. 1197 66

Based on our previous finding that chronic lithium treatment reduced naloxone-precipitated withdrawal syndrome in morphine-treated mice, the effect of chronic lithium treatment was evaluated on the development of dependence to clonidine. Dependence was induced by injection of either morphine (50, 50 and 75 mg/kg, intraperitoneally with 3 hr interval for 3 consecutive days), or clonidine (2 mg/kg/day, intraperitoneally for 10 days). Naloxone (4 mg/kg, intraperitoneally) precipitated withdrawal signs in both morphine- and clonidine-treated mice. Yohimbine (5 mg/kg, intraperitoneally) precipitated withdrawal signs in the clonidine-treated mice, similar to morphine withdrawal signs; but failed to precipitate any significant sign in the morphine-treated mice. Coadministration of lithium was carried out by adding lithium chloride to drinking water (600 mg/l for 20 days; 10 days before the beginning of clonidine administration and 17 days before the administration of morphine to allow the lithium concentration to reach steady-state). The results indicated that chronic lithium administration significantly attenuated the withdrawal signs, precipitated either by yohimbine or naloxone, in clonidine-treated mice. As a conclusion, clonidine withdrawal signs are very similar to opioid withdrawal signs, and lithium is able to prevent the development of physical dependence to clonidine.
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PMID:Lithium inhibits the development of physical dependence to clonidine in mice. 1207 31

1. This study investigated the role of spinal lipoxygenase (LOX) products in the induction and expression of opioid physical dependence using behavioural assessment of withdrawal and immunostaining for CGRP and Fos protein expression in the spinal cord. 2. Administration of escalating doses (5-50 mg kg-1; i.p.) of morphine for 5 days markedly elevated CGRP-like immunoreactivity in the dorsal horn of the rat spinal cord. Naloxone (2 mg kg-1; i.p.) challenge precipitated a robust withdrawal syndrome that depleted CGRP-like immunoreactivity and increased the number of Fos-like immunoreactive neurons in the dorsal horn. 3. Intrathecal administration of NDGA (10, 20 microg), a nonselective LOX inhibitor, AA-861 (1.5, 3 microg), a 5-LOX selective inhibitor, or baicalein (1.4, 2.8 microg), a 12-LOX selective inhibitor, concurrently with systemic morphine for 5 days or as a single injection immediately preceding naloxone challenge, blocked the depletion of CGRP-like immunoreactivity, prevented increase in the number of Fos-like immunoreactive neurons in the dorsal horn, and significantly attenuated the morphine withdrawal syndrome. 4. The results of this study suggest that activity of LOX products, at the spinal level, contributes to the expression of opioid physical dependence, and that this activity may be expressed through increased sensory neuropeptide release.
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PMID:Spinal administration of lipoxygenase inhibitors suppresses behavioural and neurochemical manifestations of naloxone-precipitated opioid withdrawal. 1297 Jan 9

The recent approval of office-based treatment for opioid addiction and US Food and Drug Administration approval of buprenorphine will expand treatment options for opioid addiction. Buprenorphine is classified as a partial micro opioid agonist and a weak kappa antagonist. It has a high affinity for the micro receptor, with slow dissociation resulting in a long duration of action and an analgesic potency 25 to 40 times more potent than morphine. At higher doses, its agonist effects plateau and it begins to behave more like an antagonist, limiting the maximal analgesic effect and respiratory depression. This "ceiling effect" confers a high safety profile clinically, a low level of physical dependence, and only mild withdrawal symptoms on cessation after prolonged administration. Suboxone contains a mixture of buprenorphine and naloxone. The naloxone is poorly absorbed sublingually and is designed to discourage intravenous use. Subutex, buprenorphine only, will also be available primarily as an initial test dose. Clinicians will be using this drug for detoxification or for maintenance of opioid addiction. Patients with recent illicit opioid use may develop a mild precipitated withdrawal syndrome with the induction of buprenorphine. Acute buprenorphine intoxication may present with some diffuse mild mental status changes, mild to minimal respiratory depression, small but not pinpoint pupils, and relatively normal vital signs. Naloxone may improve respiratory depression but will have limited effect on other symptoms. Patients with significant symptoms related to buprenorphine should be admitted to the hospital for observation because symptoms will persist for 12 to 24 hours.
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PMID:Buprenorphine: a primer for emergency physicians. 1678 31

Environmental manipulations such as social housing conditions of animals may play a role in the expression of individual differences in response to drugs. This study aimed to evaluate whether isolated and grouped mice develop different degrees of morphine dependence. Isolated and grouped mice were rendered morphine dependent employing two different methods of induction: a fast or slow protocol, both reaching the same maximum daily dose (100 mg/kg). Naloxone-induced morphine withdrawal was assessed using a modified Gellert-Holtzman scale and a conditioned place aversion (CPA) procedure. Isolated animals manifested fewer signs of physical dependence than grouped mice and only those receiving two daily morphine doses presented significantly higher scores on the Gellert-Holtzman scale than controls. Similarly, in CPA, although all morphine-treated animals developed aversion, its intensity was only significantly higher than in controls in grouped animals receiving two daily doses. Analgesic response, measured with the hot-plate test, showed that isolated mice presented longer latencies to lick their paws (even without drug administration), suggesting that they had a higher level of endogenous opiates. It can be argued that isolated animals may be less sensitive to morphine than the non-isolated and therefore tolerate greater quantities or require more drug to produce the same effects. The results suggest that variability in the response to opiates could be affected by environmental manipulations.
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PMID:Isolation decreases physical and motivational aspects of morphine withdrawal. 1586 67

Studies implicate endocannabinoids in the acute and chronic actions of opioid drugs, including the genesis of physical dependence. Previous evidence suggests that spinal release of calcitonin gene-related peptide (CGRP) and activation of its receptors contribute to opioid physical dependence. The release of CGRP at the spinal level is modulated by cannabinoid (CB1)-receptors. Thus, this study examined whether CB1-receptor activity mediates changes in CGRP underlying development of opioid physical dependence. Systemic morphine administration for 5-days elevated CGRP-immunoreactivity in the rat spinal dorsal horn. In situ hybridization of dorsal root ganglion (DRG) neurons revealed an increase in CGRP mRNA during initial (day 1-3) but not later phase (day 4-5) of morphine treatment. CGRP-immunoreactivity in DRG neurons, however, was increased in the later phase of morphine treatment. Naloxone challenge to morphine-treated animals precipitated an intense withdrawal syndrome that depleted CGRP-immunoreactivity and increased Fos expression in the dorsal horn. The Fos-response primarily occurred in neurons that expressed CGRP receptor component protein (RCP) suggesting CGRP activity contributes to neuronal activation during precipitated withdrawal. Spinal slices obtained from morphine-treated animals showed higher levels of CGRP release than from saline controls. Intrathecal co-administration of CB1-receptor antagonists, AM-251 or SR141716A, with daily morphine attenuated the behavioral manifestations of withdrawal. Treatment with AM-251 also reduced the depletion of CGRP, suppressed Fos-induction, and prevented the increase in capsaicin-evoked spinal CGRP release. Altogether, this study suggests that endocannabinoid activity, expressed via CB1-receptors, contributes to the induction of opioid physical dependence through spinal modulation of CGRP.
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PMID:Spinal modulation of calcitonin gene-related peptide by endocannabinoids in the development of opioid physical dependence. 1693 24

To explore the effect of sinomenine on the nitric oxide (NO)/neural nitric oxide synthase (nNOS) system in the cerebellum and spinal cord of morphine-dependent and morphine-withdrawal Kunming mice, mice were subjected to injection of morphine with an increasing dose for 5 d, and then were treated with sinomenine (40 mg/kg, i.p.) for another 5 d. Naloxone was used to develop acute withdrawal, and the withdrawal syndromes, including teeth chattering, twisting, straightening, sneezing and ptosis, were investigated. nNOS mRNA expressions in the cerebellum and spinal cord were determined by semi-quantitative RT-PCR. nNOS activity and NO level were determined by the chemistry-colorimetry and nitrate reductase-reduction, respectively. The results obtained were as follows: (1) Sinomenine restored the decrease in body weight and alleviated the signs of morphine-withdrawal in mice. (2) Sinomenine also reduced the increases in nNOS mRNA expression and nNOS activity resulting from morphine-dependence, and simultaneously attenuated the high level of NO in both tissues following morphine-withdrawal. (3) Administration of sinomenine alone did not develop physical dependence in mice. The results obtained indicate that sinomenine may attenuate morphine addiction and significantly alleviate morphine-withdrawal symptoms, and the mechanism may be associated with the effect of sinomenine on the NO/nNOS system in the cerebellum and spinal cord.
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PMID:[Effects of sinomenine on NO/nNOS system in cerebellum and spinal cord of morphine-dependent and withdrawal mice]. 1757 82

Mitogen-activated protein kinases (MAPK) can be activated by opioids such as morphine via opioid receptor, and their activations have been observed in synaptic plasticity, learning, memory and addiction. Long-term exposure to morphine may induce physical dependence, manifested as somatic withdrawal symptoms such as diarrhea, body weight loss, jumping and headshaking, when drug is deprived. Though morphine dependence and withdrawal have been extensively studied, their molecular mechanisms have not been fully elucidated. In the present study, the physical dependence on morphine was developed in mice by an intermittent, escalating procedure of morphine injections, and was measured by the body weight loss and the behavioral signs (jumping and headshaking). We found that the mice with chronic morphine administration experienced dramatic body weight loss, compared with the saline-treated controls. Naloxone-precipitated withdrawal led to more body weight loss, compared with spontaneous withdrawal. Naloxone-precipitated withdrawal mice showed significantly aggravated morphine-withdrawal symptoms (including jumping and heading shaking), compared with spontaneous withdrawal mice. MAPK pathway activities in the frontal association cortex (FrA), accumbens nucleus (Acb) and caudate putamen (CPu) were examined to probe into molecular mechanism for morphine dependence and withdrawal. Compared with saline-treated mice, morphine-dependent mice and spontaneous withdrawal mice, naloxone-precipitated withdrawal mice showed a significantly increased ERK phosphorylation in FrA and Acb, but not in CPu. However, the activities of other protein kinases in the MAPK pathway, including p38 and JNK, showed no changes in FrA, Acb and CPu of the mice during the chronic morphine dependence and withdrawal phases. These results suggest that the ERK phosphorylation in FrA and Acb may be associated with naloxone-precipitated withdrawal syndrome.
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PMID:Naloxone-precipitated withdrawal enhances ERK phosphorylation in prefrontal association cortex and accumbens nucleus of morphine-dependent mice. 1992 70


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