Cyclo-oxygenase-inhibitors increase morphine effects on mesolimbic dopamine neurons

doi:10.1016/S0014-2999(99)00799-2

European Journal of Pharmacology

Volume 387, Issue 1, 3 November 2000, Pages R1-R3

https://doi.org/10.1016/S0014-2999(99)00799-2 Get rights and content

Abstract

The effect of cyclo-oxygenase inhibitors, indomethacin and nimesulide, on the action of i.v. morphine on dopamine neurons projecting to the nucleus Accumbens was studied using standard extracellular recording techniques coupled with antidromic identification in unanesthetized rats. The i.v. administration of either nimesulide (3 mg/kg) or indomethacin (3.5 mg/kg) per se did not affect the firing rate of mesolimbic dopamine cells. In contrast, the subsequent administration of morphine (0.25–2 mg/kg i.v.) potently increased the firing rate of mesolimbic dopamine neurons in cyclo-oxygenase inhibitor-pretreated rats as compared with saline-pretreated rats. The maximal enhancement of basal firing rate at the highest dose of morphine tested was 92%, 80% and 47%, for nimesulide-, indomethacin-, and saline-treated rats, respectively. Our results indicate that the effect of morphine on mesolimbic dopamine cells is potentiated by blocking cyclo-oxygenase activity and suggest that the modulation of cyclo-oxygenase pathway in dopamine cells might be involved in the cellular mechanisms of the rewarding actions of morphine.

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Acknowledgements

The authors thank Mr. Stefano Aramo for his skillful technical assistance.

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Citation Excerpt :
In the same model, it is found that COX enzymes inhibitors attenuate expression of dependence to μ and κ- receptor agonists [113]. Several studies have also reported that COX pathway has greatly contributed in modulation of GABA and dopamine, two neurotransmitters involved in reinforcing- and rewarding mechanisms [101,103,114–116]. In addition, recent findings have supported the idea that COX pathway activation and prostaglandin production contribute to the rewarding process due to morphine administration in place preference task [117].
There is no denying that opioids are the most important analgesic drugs which are widely used in clinical situations. Still, prolonged administration of these drugs can cause to reduce their analgesic efficacy due to the development of tolerance. These drugs can also cause induction of hyperalgesia. In addition, long-term administration of opioids through reinforcing- and rewarding pathways of limbic system can result in expression of opioid dependence with the unintended consequences of opioid abuse/misuse and finally opioid addiction. As studies show, over-activity in cyclo-oxygenase pathways and production of prostaglandins due to long-term exposures of opioid have a critical role in the development of tolerance to antinociceptive effect of opioid, hyperalgesia, and opioid dependence. The present study aims at suggesting the hypothesis that through blending a non-steroid anti-inflammatory drug with opioid actively causes reduction in unwanted effects of opioid i.e. by inhibition of opioid-induced cyclo-oxygenase overactivity whereas it is well-known that the combination therapy via reducing opioid dosage reduces the unwanted effects.
Inhibition of the cyclooxygenase pathway attenuates morphine-induced conditioned place preference in mice
2006, Pharmacology Biochemistry and Behavior
Prostanoids are shown to be important lipid mediators, not only in periphery but also in the brain, where they appear to modulate synaptic transmission. Recent studies have demonstrated that cyclooxygenase (COX) pathway might modulate the neurotransmission of γ-aminobutyric acid and dopamine in the central nervous system. In this study, we have evaluated the effects of indomethacin (a non-selective COX inhibitor) and celecoxib (a selective COX-2 inhibitor) on the acquisition of morphine-induced conditioned place preference (CPP) in male Swiss mice. Our data shows that morphine (2.5–7.5 mg/kg) induces place preference conditioning in a dose-dependent manner. Celecoxib (0.01–5 mg/kg) and indomethacin (1 mg/kg) fail to produce a significant CPP or conditioned place aversion (CPA); however, higher doses of celecoxib (10 mg/kg) and indomethacin (5 mg/kg) induce CPA. Co-administration of celecoxib (0.5–5 mg/kg) or indomethacin (1–5 mg/kg) with morphine during the conditioning phase, blocked the acquisition of morphine CPP. These results indicate that the reward properties of morphine can be modulated by inhibiting COX activity in mice.
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We have reported that subeffective doses of the nonsteroidal anti-inflammatory drug (NSAID) dexketoprofen trometamol enhances μ-opioid receptor agonist fentanyl antinociception. The aim of this study was to assess if this effect can also be observed with other new cyclooxygenase-inhibitors such as nitroparacetamol, and in responses to high intensity electrical stimulation (wind-up). Single motor units were recorded in male Wistar rats under α-chloralose anaesthesia. The antinociceptive effect of fentanyl was studied alone and in the presence of subeffective doses of dexketoprofen trometamol or nitroparacetamol. In responses to noxious mechanical stimulation, the potency of fentanyl was enhanced by more than threefold in the presence of the NSAIDs and no significant recovery was observed after 45 min. The opioid antagonist naloxone and the α₂-adrenoceptor antagonist atipamezol did not reverse the effect. The enhancement of the effect of fentanyl in wind-up was lower though significant. We conclude that the co-administration of subeffective doses of new cyclooxygenase-inhibitors and the μ-opioid receptor agonist fentanyl should be considered as a potential pain therapy.
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Rapid communicationCyclo-oxygenase-inhibitors increase morphine effects on mesolimbic dopamine neurons

Abstract

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Acknowledgements

Brain Res.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neuroscience

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Cyclo-oxygenase-inhibitors increase morphine effects on mesolimbic dopamine neurons