Naloxone-precipitated Morphine Withdrawal In Mice Research Articles

Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents

Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

Noradrenergic and corticosteroid receptors regulate somatic and motivational symptoms of morphine withdrawal

Somatic and motivational symptoms accompanying opiate withdrawal are considered one of the major reasons for relapse to opiate-seeking and opiate-taking behaviors. These symptoms are accompanied by the activation of stress-related processes including hypothalamic-pituitary-adrenal axis activity and noradrenergic (NA) signaling. In particular, the NA system plays an important role in the expression of somatic signs of opiate withdrawal, whereas glucocorticoid (GR) and mineralocorticoid receptors (MR) are activated during opiate abstinence.The purpose of our study was to examine the roles of α1-, α2-, and β-adrenoceptors (ARs) as well as GR and MR, in the formation and expression of physiological and motivational symptoms of morphine withdrawal. We showed that systemic pretreatment with the selective α1-AR antagonist prazosin (0–1 mg/kg), the selective α2-AR antagonist RX821002 (0–2 mg/kg), the selective β-adrenergic antagonist, propranolol (0–10 mg/kg), or the selective MR antagonist spironolactone (0–50 mg/kg), but not the selective GR antagonist mifepristone (0–40 mg/kg), decreased somatic symptoms of naloxone-precipitated morphine withdrawal in mice chronically treated with morphine. In contrast, only propranolol pretreatment attenuated the dysphoric affective state accompanying naloxone-precipitated morphine withdrawal as assessed in the conditioned place aversion (N-CPA) paradigm.Together, our results demonstrate the important roles of noradrenergic receptors in the modulation of somatic, but not motivational/affective, symptoms of morphine withdrawal. In addition MR but not GR regulates the expression of only somatic symptoms of morphine withdrawal.

Geraniin attenuates naloxone-precipitated morphine withdrawal and morphine-induced tolerance in mice.

Potentially life-threatening and unpleasant side effects associated with some analgesics have fueled the drive for the search for more analgesics with better side effect profiles. Geraniin, the most dominant secondary metabolite in the aqueous extract of the aerial parts of Phyllanthus muellerianus, has been shown to possess antinociceptive properties mediated partly by opioidergic mechanisms. The purpose of this study is to determine whether geraniin exhibits tolerance and if it is able to ameliorate withdrawal signs in naloxone-precipitated morphine withdrawal. After chronic treatment of mice with geraniin orally, the formalin test was used to ascertain whether tolerance will develop to its antinociceptive effects and if there is morphine-induced tolerance cross-generalization with geraniin. The effect of geraniin on naloxone-precipitated morphine withdrawal signs in morphine-dependent mice was also investigated. Geraniin (3-30 mg/kg) did not produce any tolerant effects after chronic administration and there was also no cross-generalization with the tolerant effects of morphine. Geraniin did not induce withdrawal signs but significantly reduced the number of jumps in morphine-dependent mice. Geraniin does not produce any tolerant effects like morphine and also reduced the signs associated with naloxone-precipitated morphine withdrawal in mice.

The CB1 Receptor Antagonist, AM281, Improves Recognition Loss Induced by Naloxone in Morphine Withdrawal Mice

Morphine withdrawal leads to the activation of endocannabinoid system and cognitive deficits. The aim of this study was to evaluate the effects of AM281, a cannabinoid antagonist/inverse agonist, on memory deficit following naloxone-precipitated morphine withdrawal in mice. Male mice were made dependent by increasing doses of morphine (30-90mg/kg) twice daily for 3days. The object recognition task was used to evaluate memory dysfunction. The test comprised three sections: habituation for 15min., first trial for 12min. and test trial for 5min. In this learning paradigm, the difference in exploration between a previously seen object and a new object is taken as an index of memory performance (recognition index). The recognition index was assessed on the third day of morphine treatment by the injection of 0.1mg/kg naloxone 3hr after the last dose of morphine. Chronic administration of AM281 at 2.5mg/kg significantly improved the memory impairment, producing a recognition index of 36.0±3.9 as compared with vehicle-treated data (recognition index=-3.1±8.2%). A single dose of AM281 at 5mg/kg improved the recognition index from -1.5±3.9% in morphine withdrawal animals to 18.5±11.6%. Concurrent administration of AM281 with morphine proved to be more effective in protecting the animals from losing their memory compared to acute action of AM281. These results indicate that the contribution of the cannabinoid system to memory deficit is attributable to morphine withdrawal. By blocking cannabinoid receptors, AM281 may become useful in preventing memory deficit after morphine withdrawal.

Suppressive effects of dichloromethane fraction from the Areca catechu nut on naloxone-precipitated morphine withdrawal in mice

In the present study, we investigated the effect of the dichloromethane fraction from Areca catechu nut on the severity of naloxone-precipitated morphine withdrawal in morphine-dependent mice. A single intraperitoneal injection of dichloromethane fraction at dose of 125 and 175 mg/kg significantly delayed the onset of withdrawal jumping behavior in a concentration-dependent manner compared to that of saline controls. The dichloromethane fractions also significantly decreased jumping numbers and faecal and urinary excretions during the withdrawal period.

Inhibition of morphine withdrawal by lamotrigine: involvement of nitric oxide

We studied the effects of lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine], a new antiepileptic compound, on naloxone-precipitated morphine withdrawal in mice. Pretreatment with lamotrigine (5–100 mg/kg, s.c.) reversed in a dose-dependent way the withdrawal-induced increase in cerebellar Ca 2+-dependent nitric oxide (NO) synthase activity and reduced the number of escape jumps and other motor symptoms of abstinence, at doses that did not modify locomotor activity (25–50 mg/kg). Pretreatment with the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5 H-dibenzo[ a,d]cyclohepten-5,10-imine; dizocilpine] (0.1–0.3 mg/kg, s.c.) also reversed the increase in cerebellar Ca 2+-dependent NO synthase activity. However, although MK-801 reduced the number of escape jumps and other motor symptoms of abstinence, its effects were not clearly dose-dependent. Furthermore, the highest dose of MK-801 tested (0.3 mg/kg) caused an impairment of the locomotor behaviour in naive mice. Thus, lamotrigine may represent a new and useful agent for the treatment of opiate abstinence.

Effects of ethylenediamine on morphine analgesia and tolerance-dependence in mice

1. 1.|Ethylenediamine, a GABA receptor agonist induced a small hyperalgesic state in mice, but increased morphine analgesia. The interaction with this morphine effect was not dose-dependent. 2. 2.|Ethylenediamine significantly antagonized tolerance development at relatively low doses (5–10 mg/kg). 3. 3.|The GABA mimetic agent increased the frequency of abstinence signs in the naloxone-precipitated morphine withdrawal in mice. 4. 4.|The effect of ethylenediamine on morphine withdrawal was suppressed by the irreversible GABA transaminase inhibitor, γ-vinyl GABA.