Morphine Withdrawal Research Articles

Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment

This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT.

Inter-individual differences in serotonin and glutamate co-transmission reflect differentiation in context-induced conditioned 50-kHz USVs response after morphine withdrawal

A growing body of research provides compelling evidence that in rats 50-kHz USVs are a form of expression of positive emotions. Context-induced 50-kHz USVs emission is variable among rats, indicating individual differences in contextual response bound up with pharmacological reward. The aims of this study were to: extract the most important neurotransmitters related to context-induced conditioned 50-kHz USVs response; find biological basis of existing inter-individual differences in context-induced conditioned 50-kHz USVs response; create a model of all-to-all neurotransmitters correlations. The data collected here confirms that re-exposure to the context of morphine administration after the withdrawal period increases the level of 50-kHz USVs and this contextual response is associated with elevated serotonin concentrations in amygdala, hippocampus and mPFC and with increased Glu/Gln ratio in nucleus accumbens. The concentration of serotonin increases simultaneously in amygdala, nucleus accumbens and hippocampus. Moreover, 5-HT concentration in amygdala is bound up with glutamate level in this structure as well as in hippocampus. Furthermore, Glu/Gln ratio in nucleus accumbens has strong associations with Glu/Gln ratio simultaneously in VTA, amygdala, striatum and hippocampus. All-to-all-analysis indicate that concentration of glutamate in hippocampus is proportional to glutamate in VTA and GABA concentration in the hippocampus. We have also demonstrated that Glu/GABA ratio in VTA and amygdala was elevated after post withdrawal re-exposure to the pharmacological reward paired context. Presented analysis indicates a strong correlation between serotonergic and glutamatergic systems in context-induced conditioned response. The strength of this co-transmission correlates with the number of 50-kHz USVs emitted in response to morphine-paired context.

Effects of acute morphine withdrawal on ultrasonic vocalizations in adult rats: unchanged 50-kHz call rate and altered subtype profile.

Adult rat 22- and 50-kHz ultrasonic vocalizations (USVs) are commonly considered as indices of negative and positive affect, respectively. More specifically, we have proposed that positive affective states are revealed by a predominance of trill over flat 50-kHz call subtypes. However, the 50-kHz call subtypes emitted during aversive drug states remain largely uninvestigated. To determine whether acute morphine withdrawal affects 50-kHz call rates or alters the relative prevalence of trill and flat calls. In experiment 1, adult male rats were given saline or morphine (6mg/kg SC), then acutely challenged 4h later with saline or naloxone (1mg/kg SC), and recorded 10-30min post-injection. In experiments 2 and 3, rats received saline or morphine (6mg/kg), followed 4h later by acute saline or naloxone (0.1mg/kg) challenge; USVs were subsequently recorded during 30-min place conditioning sessions. Naloxone (0.1mg/kg) produced a strong conditioned place aversion only after acute morphine pretreatment, consistent with antagonist-precipitated morphine withdrawal. The morphine-naloxone combination decreased the relative prevalence of trills and promoted flat calls. Naloxone given alone (0.1 and 1mg/kg) inhibited trill calls but did not significantly alter the prevalence of flat calls, whereas morphine given alone (4h pre-session) was largely without effect. Fifty-kHz call rates were inhibited by naloxone given alone, but otherwise unaffected. Twenty-two-kHz calls were sparse. The 50-kHz call subtype shift seen during antagonist-precipitated morphine withdrawal was opposite in direction to that previously associated with rewards, and hence may reveal negative affect.

Effect of Hydro-alcoholic extract of Jasminum sambac on morphine withdrawal symptoms in rats

Effect of Hydro-alcoholic extract of Jasminum sambac on morphine withdrawal symptoms in rats

Effect of Hydro-alcoholic extract of Jasminum sambac on morphine withdrawal symptoms in rats

Effect of Hydro-alcoholic extract of Jasminum sambac on morphine withdrawal symptoms in rats

Hippocampal glial cells modulate morphine-induced behavioral responses

Drugs of abuse cause persistent alterations in synaptic plasticity that is thought to underlie addictive-like behaviors. Although, the perisynaptic glial cells are implicated in metabolic maintenance and support of the nervous systems, accumulating evidence suggests that glial cells exert a modulatory action on synaptic functions and participate in synaptic plasticity. However, it is well-documented that glial cells are associated with the acquisition of rewarding effects of abused drugs. The role of hippocampal glial cells in addictive-like behaviors remains poorly understood. In this study, we investigated the role of hippocampal glial cells in morphine-induced behavioral responses including morphine dependence, tolerance to the antinociceptive properties of morphine, and conditioned place preference (CPP). Male rats received subcutaneous (s.c.) morphine sulfate (10 mg/kg) at an interval of 12 h for 9 days. To suppress glial cells activity, the animals received microinjection of fluorocitrate (FC, a metabolic inhibitor of glial cells) into the CA1 region before each morphine administration. The animals were assessed for morphine dependence by monitoring naloxone hydrochloride-induced precipitation of somatic signs of morphine withdrawal. The tolerance to the antinociceptive effects of morphine and morphine-induced CPP were measured in a separate set of experimental groups. We found animals receiving FC before morphine injection demonstrated a significant reduction in several signs of morphine withdrawal such as freezing, defecation, chewing, explosive running, ptosis, activity, scratching, wet dog shake, and writhing. Inhibition of glial cells caused a significant reduction of tolerance to the antinociceptive effect of morphine. Finally, intra-CA1 administration of FC decreased morphine-induced CPP. Our findings suggest that hippocampal glial cells may be involved in morphine-induced behavioral responses.

Over-expression of CCK1 Receptor Reverse Morphine Dependence

Studies demonstrated that cholecystokinin (CCK) system involved in morphine dependence and withdrawal. Our previous study showed that endogenous CCK system were up-regulated after chronic morphine exposure. Additionally, CCK1 receptor significantly blocked the inhibitory effect of exogenous CCK-8 on morphine dependence, but CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence. Therefore, CCK1R and CCK2R function differently in chronic morphine dependence, but the mechanism is still unclear. In this study, HEK-293 cells co-transfected with µ-opioid receptors (HEK293-hMOR) and CCK1R or CCK2R were established. Cells were treated with 10 µM morphine for 6, 12, 16, 24 h and 100 µM naloxone precipitation for 15 min. cAMP overshoot was appeared at 12 h and was increased time dependently after morphine exposure in HEK293-hMOR cells. The cAMP overshoot did not appear in CCK1R-overexpressing HEK293-hMOR cells, while still appeared in CCK2R-overexpressing HEK293-hMOR cells. Over-expression of CCK1R reversed CREB and ERK1/2 activation in HEK293-hMOR cells exposed to morphine. Our study identifies over-expression of CCK1R significantly blocked morphine dependence, which was related with phosphorylation of CREB, and ERK1/2 signaling activation. While over-expression of CCK2R promoted morphine dependence, which was related with phosphorylation of CREB but not ERK1/2 signaling activation.

Social transfer of alcohol withdrawal-induced hyperalgesia in female prairie voles

ABSTRACTThe expression of pain serves as a way for animals to communicate potential dangers to nearby conspecifics. Recent research demonstrated that mice undergoing alcohol or morphine withdrawal, or inflammation, could socially communicate their hyperalgesia to nearby mice. However, it is unknown whether such social transfer of hyperalgesia can be observed in other species of rodents. Therefore, the present study investigated if the social transfer of hyperalgesia occurs in the highly social prairie vole (Microtus ochrogaster). We observe that adult female prairie voles undergoing withdrawal from voluntary two-bottle choice alcohol drinking display an increase in nociception. This alcohol withdrawal-induced hypersensitiity is socially transferred to female siblings within the same cage and female strangers housed in separate cages within the same room. These experiments reveal that the social transfer of pain phenomenon is not specific to inbred mouse strains and that prairie voles display alcohol withdrawal and social transfer-induced hyperalgesia.

Chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in basolateral amygdala neurons that project to prelimbic cortex

Drug addiction is a brain disorder characterized by chronic, compulsive use of drugs. Previous studies have found a number of chronic morphine-induced changes in the brain at molecular levels. A study from our lab showed that chronic morphine-induced increase in the expression of presynaptic D1 receptors in basolateral amygdala (BLA) neurons played an important role in environmental cue-induced retrieval of morphine withdrawal memory. However, the downstream neurocircuitry of chronic morphine-induced increase presynaptic D1 receptors in the BLA remains to be elucidated. Using retrogradely labelling technique combined with whole-cell patch-clamp methods, our results showed that (1) chronic morphine sensitized the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that projected to the prelimbic cortex (PrL), but had no influence on that in BLA neurons that projected to the nucleus accumbens (NAc) or the CA1 of the hippocampus; (2) chronic morphine sensitized the effect of D1 receptor agonist on action potential firing in BLA neurons that projected to the PrL, but without affecting the intrinsic excitability and the sensitivity of postsynaptic glutamate receptors to glutamate in BLA neurons that projected to the PrL. These results suggest that chronic morphine selectively sensitizes the effect of D1 receptor agonist on presynaptic glutamate release in BLA neurons that project to PrL and induces a sensitization of the effect of D1 receptor agonist on action potential firing in BLA neurons that project to the PrL.

The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice

Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade.Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse to drug-seeking/taking behavior triggered by opiate withdrawal-associated aversive memories.

Evaluation of opioid withdrawal after drug cessation in morphine and mitragynine dependent rats

Event Abstract Back to Event Evaluation of opioid withdrawal after drug cessation in morphine and mitragynine dependent rats RAHIMAH HASSAN1, Sharif M. Mansor1 and Zurina Hassan1* 1 University of Science, Malaysia, Malaysia Background Mitragynine is an indole alkaloid found in Mitragyna speciosa or known as Kratom. It is native in Southeast Asia and originally used for its therapeutic effects and as a substitution in self-treatment of opiate addiction. However, mitragynine consumption develops drug dependence. Hence, the present study aims to evaluate drug dependence after drug cessation via spontaneous withdrawal symptoms in morphine and mitragynine dependent rats. Methods Morphine dependent rats were developed by increasing the doses (mg/kg and shown in bracket) twice daily for 6 consecutive days: 1st day (0, 10), 2nd day (10, 10), 3rd day (20, 20), 4th day (30, 30), 5th day (40, 40), 6th day (50, 50). Morphine treatment was disrupted on day 7 in order to induce spontaneous opiate abstinence. For mitragynine dependent rats, 30 mg/kg were given daily for 14 days and disrupted on day 15. The assessment of physical dependence of morphine, mitragynine and control groups were based on motor and vegetative signs. The signs of spontaneous withdrawal symptoms were recorded for 30 minutes in an open field test chamber, 24 hours after the last dose for 28 days. The 'counted signs' and 'checked signs' were multiplied with the respective 'weighing factors' for the evaluation of the severity of abstinence syndrome. Results The morphine dependent rats develop opioid withdrawal by significantly increase the mean aggregate value of spontaneous withdrawal symptoms. The morphine withdrawal symptoms last for 16 days after drug cessation. However, the spontaneous withdrawal symptoms of mitragynine dependent rats reduced by half on the 2nd day after drug cessation and last for 9 days. Conclusion Spontaneous withdrawal symptoms in mitragynine dependent rats was found to be resolved in shorten period compared to morphine dependence rats. Acknowledgements This project is funded by HICoE Ministry of Education Special Grant 304.CDADAH.4401009 Keywords: mitragynine, Morphine, Opioid withdrawal, Drug cessation, spontaneous withdrawal symptoms Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Poster Presentation Topic: Mental health Citation: HASSAN R, Mansor SM and Hassan Z (2019). Evaluation of opioid withdrawal after drug cessation in morphine and mitragynine dependent rats. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00071 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Sep 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Zurina Hassan, University of Science, Malaysia, George Town, Malaysia, zurina_hassan@usm.my Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers RAHIMAH HASSAN Sharif M Mansor Zurina Hassan Google RAHIMAH HASSAN Sharif M Mansor Zurina Hassan Google Scholar RAHIMAH HASSAN Sharif M Mansor Zurina Hassan PubMed RAHIMAH HASSAN Sharif M Mansor Zurina Hassan Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Effects of BDNF receptor antagonist on the severity of physical and psychological dependence, morphine-induced locomotor sensitization and the ventral tegmental area-nucleus accumbens BDNF levels in morphine- dependent and withdrawn rats

This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) on the severity of physical and psychological dependence and morphine-induced locomotor sensitization, the ventral tegmental area (VTA)-nucleus accumbens (NAc) BDNF levels in morphine-dependent and withdrawn rats. Rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 10 days. Then, rats were tested for naloxone-precipitated morphine withdrawal signs, the anxiety (the elevated plus maze-EPM) after the last morphine injection and injection of ANA12 (ip). Also, morphine-induced locomotor sensitization was evaluated after morphine challenge followed by an injection of ANA-12 in morphine-withdrawn rats. The VTA-NAc BDNF levels were assessed in morphine-dependent and withdrawn rats. The overall Gellert–Holtzman score was significantly higher in morphine-dependent rats receiving ANA-12 than in those receiving saline. Also, the percentage of time spent in the open arms in control and morphine-dependent rats receiving ANA-12 were higher compared to the Cont/Sal and D/Sal rats, respectively. There was no significant difference in the locomotor activity and the VTA-NAc BDNF levels between D/Sal/morphine and D/ANA-12/morphine groups after morphine withdrawal. We conclude that the systemic administration of ANA-12 exacerbates the severity of physical dependence on morphine and partially attenuates the anxiety-like behavior in morphine-dependent rats. However, ANA-12 did not affect morphine-induced locomotor sensitization and the VTA-NAc BDNF levels in morphine-dependent and withdrawn rats.

Pharmacological and Toxicological Profile of Harmane-β-Carboline Alkaloid: Friend or Foe.

The plant secondary metabolites have an outstanding therapeutic potential and success over the years. In fact, it is the foundation of numerous clinically used drugs. Similarly, these is a general perception that these products are inherent safety. However, such products might have toxic/unwanted lethal effects therefore, along with biological relevance, toxicological evaluation is equally important for clinical applications. Therefore, harmane- β-carboline alkaloid was investigated for both therapeutic and toxicological potential. The literature related to the therapeutic/toxicological effects of the alkaloid was searched using various scientific data bases including Google, ScienceDirect, PubMed, SpringerLink, ASC. The peer reviewed articles were only selected. The harmane-β-carboline alkaloid has shown several pharmacological activities such as antianxiety, antidepressant, antiplatelet, antidiabetic, acetylcholinesterase and myeloperoxidase inhibition, antioxidant, antiparasitic, hypotensive, morphine withdrawal syndrome alleviation, and antinociceptive effects. On the other hand, it exhibited tremorogenic effect, for a symptom of Parkinson's disease. Adverse effect of the alkaloid on learning and memory have also been observed. All together, it is, concluded in this review that harmane elicited marked pharmacological effects but simultaneously, it possessed some serious side effects that could be the primary hurdle in the way of its clinical testing.

Memory retrieval in addiction: a role for miR-105-mediated regulation of D1 receptors in mPFC neurons projecting to the basolateral amygdala

BackgroundDrug addiction is a chronic brain disorder characterized by the compulsive use of drugs. The study of chronic morphine-induced adaptation in the brain and its functional significance is of importance to understand the mechanism of morphine addiction. Previous studies have found a number of chronic morphine-induced adaptive changes at molecular levels in the brain. A study from our lab showed that chronic morphine-induced increases in the expression of D1 receptors at presynaptic terminals coming from other structures to the basolateral amygdala (BLA) played an important role in environmental cue-induced retrieval of morphine withdrawal memory. However, the neurocircuitry where the increased D1 receptors are located and how chronic morphine increases D1 receptor expression in specific neurocircuits remain to be elucidated.ResultsOur results show that chronic morphine induces a persistent increase in D1 receptor expression in glutamatergic terminals of projection neurons from the medial prefrontal cortex (mPFC) to the BLA, but has no influence on D1 receptor expression in projection neurons from the hippocampus or the thalamus to the BLA. This adaptation to chronic morphine is mediated by reduced expression of miR-105 in the mPFC, which results in enhanced D1 receptor expression in glutamatergic terminals of projection neurons from the mPFC to the BLA. Ex vivo optogenetic experiments show that a chronic morphine-induced increase in D1 receptor expression in glutamatergic terminals of projection neurons from the mPFC to the BLA results in sensitization of the effect of D1 receptor agonist on presynaptic glutamate release. mPFC to BLA projection neurons are activated by withdrawal-associated environmental cues in morphine-withdrawal rats, and overexpression of miR-105 in the mPFC leads to reduced D1 receptor induction in response to chronic morphine in glutamatergic terminals of the projection neurons from the mPFC to the BLA, and a reduction in place aversion conditioned by morphine withdrawal.ConclusionsThese results suggest that chronic morphine use induces a persistent increase in D1 receptors in glutamatergic terminals of projection neurons from the mPFC to the BLA via downregulation of miR-105 in the mPFC, and that these adaptive changes contribute to environmental cue-induced retrieval of morphine withdrawal memory.

Cupping: a reasonable choice for attenuating morphine withdrawal symptoms in Wistar rats

Background: Nowadays, the sedative drugs are the main treatments to attenuate the opioid withdrawal symptoms. However, physical therapies are found a safe alternative treatment without any serious adverse effects. This study aimed to evaluate the effects of cupping treatment on the morphine withdrawal symptoms in rats.Methods: Eighty rats were divided into two main groups; treated with morphine or saline, and each group was also divided to cupping and sham cupping subgroups (with single or daily treatment). Injection of morphine and saline were done in the morphine and saline groups twice a day for nine days. On the ninth day, the naloxone was administered and the withdrawal symptoms including jumping, rearing, body grooming, abdominal writing, and wet-dog shaking were recorded for 60 minutes. Cupping or sham cupping was applied on the GV14 once before or daily after withdrawal induction in each group.Results: The results revealed that a single cupping before the withdrawal induction significantly attenuated the withdrawal symptoms in the morphine group (p<0.01).But, the daily cupping failed to decrease the withdrawal symptoms in this group. The results also indicated that the daily cupping in the saline group increased the naloxone-induced withdrawal symptoms significantly (p<0.01).Conclusions: Single session cupping before the withdrawal induction could decreased the withdrawal symptoms. This finding might be related to the modulation of GABAergic system.

P.1.d.003 - The role of astrocytic glucocorticoid receptor in morphine withdrawal and conditioned place aversion

P.1.d.003 - The role of astrocytic glucocorticoid receptor in morphine withdrawal and conditioned place aversion

P.6.c.016 - BDNF alterations in nucleus accumbens shell during morphine withdrawal

The present paper reports the results of two corpus studies of multi-word verbs in the context of Cognitive Construction Grammar. The main claim of the constructionist approach adopted in this paper is that the meaning of specific multi-word verbs (MWVs), that is, combinations of a verb proper and a particle (spatial adverb, preposition, or both), overlaps the meaning of the argument structure construction in which it appears, thereby facilitating the positing of motivated categories. This theoretical claim is supported by the results of a two-staged corpus study. The first part of the study uses the affordances of the online interface of the 520-million-word Corpus of Contemporary American English (COCA). The results show that the identified MWVs in the corpus are skewed toward motional usages in spoken registers. The list of frequent MWVs provides the data for the second study. In this case, the results confirm the hypothesis that MWVs overlap specific argument structure constructions following distinct attachment patterns. This finding also suggests that argument structure constructions are high-order constructions that interface thought and language at a deep cognitive level.

Central antagonism of orexin type-1 receptors attenuates the development of morphine dependence in rat locus coeruleus neurons

Prolonged use/abuse of opioid agonists leads to development of severe dependence to these drugs. Orexin-A has a crucial role in development of morphine dependence. The locus coeruleus (LC) is implicated in the expression of morphine withdrawal signs. Hyperactivity of LC neurons as well as increased intracellular cyclic adenosine monophosphate (cAMP) level temporally corresponds to the expression of opioid withdrawal behaviors. In this study the effect of central OX1R blockade on neuronal activity and cAMP content of LC neurons was investigated following naloxone administration in morphine-dependent rats. Male Wistar rats weighing 250–300g were used in this study. To induce morphine dependence, morphine was injected intraperitoneally (10mg/kg, i.p.) once a day for seven consecutive days. A selective OX1R antagonist (SB-334867) was microinjected into the cerebral ventricle (10µg/10µl) immediately before each morphine injection. The activity of LC neurons was investigated using in vivo extracellular single-unit recording on day 8 and naloxone (2mg/kg, i.p.) was administered after 10-min baseline recording. In addition, immunohistofluorescence method was used to measure the effect of naloxone on coerulear cAMP level. Chronic morphine injection induced morphine dependence in LC neurons which was revealed as a significant increase in LC neuronal firing rate in response to naloxone. The results of this study indicated that SB-334867 administration prior to each morphine injection prevents naloxone-elicited neuronal activation within the LC. In addition, naloxone injection enhanced the cAMP concentration in LC neurons of morphine-dependent animals and this effect was significantly reduced by OX1R blockade.

Effect of the methanolic extracts of different parts of Ferula assa-foetida on naloxone-induced withdrawal behavior in morphine-dependent mice.

Ferula assa-foetida, a native species in Iran, is used for treatment of several diseases particularly for neurological disorders in Iranian Traditional Medicine. The aim of this study is to investigate the effect of methanolic roots, fruits, and aerial parts extracts of Ferula assa-foetida on withdrawal syndrome in morphine-dependent mice. Aerial parts, roots, and fruits of the plant were separately extracted with 80% MeOH. For induction of dependence, morphine (50, 50 and 75 mg/kg) was injected subcutaneously three times daily (10 am, 1 pm and 4 pm) for three days and a last dose of morphine (50 mg/kg) was administrated on the fourth day. Withdrawal syndrome was induced by injection of naloxone (5 mg/kg, intraperitoneal) 2 hr after the final dose of morphine. Different doses of the extracts were administered i.p. 60 minutes before naloxone injection and withdrawal sign was recorded 2 minutes after naloxone injection for a period of 60 minutes. Pre-treatment of animals with different doses (2.5, 5, 10, 20 mg/kg) of methanolic extract of the aerial parts of F. assa-foetida caused a significant decrease in naloxone-induced behavior. Intraperitoneal administration of different doses (10, 15, 20, 25 mg/kg) of methanolic extract of the fruit significantly reduced the naloxone-induced withdrawal behavior (p<0.001). It might be concluded that the extracts of Ferula assa-foetida affect morphine withdrawal syndrome possibly via interference with the neurotransmitters in nervous system.

Genetic deletion of microglial Panx1 attenuates morphine withdrawal, but not analgesic tolerance or hyperalgesia in mice

ABSTRACTOpioids are among the most powerful analgesics for managing pain, yet their repeated use can lead to the development of severe adverse effects. In a recent study, we identified the microglial pannexin-1 channel (Panx1) as a critical substrate for opioid withdrawal. Here, we investigated whether microglial Panx1 contributes to opioid-induced hyperalgesia (OIH) and opioid analgesic tolerance using mice with a tamoxifen-inducible deletion of microglial Panx1. We determined that escalating doses of morphine resulted in thermal pain hypersensitivity in both Panx1-expressing and microglial Panx1-deficient mice. In microglial Panx1-deficient mice, we also found that acute morphine antinociception remained intact, and repeated morphine treatment at a constant dose resulted in a progressive decline in morphine antinociception and a reduction in morphine potency. This reduction in morphine antinociceptive potency was indistinguishable from that observed in Panx1-expressing mice. Notably, morphine tolerant animals displayed increased spinal microglial reactivity, but no change of microglial Panx1 expression. Collectively, our findings indicate microglial Panx1 differentially contributes to opioid withdrawal, but not the development of opioid-induced hyperalgesia or tolerance.