Dopamine receptor mechanism(s) and morphine tolerance in mice

Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Morphine is a highly efficacious agent against chronic severe pain. However, repeated morphine administration leads to antinociceptive tolerance which discontinues morphine therapy for chronic pain. The cellular and molecular mechanisms underlying morphine tolerance are still not fully understood. Morphine is known to exert analgesic effect mainly by activating MOR encoded by the MOR-1 gene. And in MOR-1 knockout mice, the analgesia and tolerance of morphine are absent 1,2 . These results suggested that morphine tolerance may be partly mediated by MOR and it has been reported that MOR desensitization 3,4 contributes to the development of morphine tolerance. In addition, central sensitization also promotes the development and maintenance of morphine tolerance. Chronic morphine treatment can significantly increase the release of different neurotransmitters such as glutamate (Glu), which binds to the NMDA receptor to enhance the excitatory synaptic transmission 5,6 . It also activates the astrocytes and microglia 7-9 , leading to the release of the pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα ) and interleukin-1β (IL-1β ) 10-12 to promote the morphine tolerance.D2DR, a dopamine receptor subtype which affects the locomotion, reward and abuse of opioids [13][14][15][16] has been reported to be involved in morphine-induced nociception modulation in rats. Activation of D2DR by quinpirole in hypothalamic A11 cell group 17 , ventrolateral orbital cortex (VLO) 18 and dorsal hippocampus (CA1) 19 of rats exerts antinociceptive effect. Intraperitoneal injection of quinpirole enhances the antinociceptive effect of morphine 20 . However, Michael A. King and colleagues reported that the effect of opioid analegesia is potentiated in D2DR knock-out mice 21 . Therefore, the apparent analgesia effect and mechanism of D2DR were still not clear. And the effect and mechanism of D2DR on morphine tolerance has also not been elucidated.The present study was performed to investigate the possible role of D2DR in morphine tolerance at spinal levels of mice. Our results indicated that chronic morphine treatment increased the neuronal D2DR expression

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“…Others recommended that both D2DR agonist quinpirole (i.p. )20 and D2DR antagonist sulpiride (i.p. )20, eticloride (i.p.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of D2DR by quinpirole in hypothalamic A11 cell group17, ventrolateral orbital cortex (VLO)18 and dorsal hippocampus (CA1)19 of rats exerts antinociceptive effect. Intraperitoneal injection of quinpirole enhances the antinociceptive effect of morphine20. However, Michael A.…”

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confidence: 99%

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

Dai

Xiong

Yan

et al. 2016

Sci Rep

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“…Dopamine receptor agonists as well as antagonists have been shown to modulate the analgesic effects of morphine in animal models (Zarrindast et al 1999(Zarrindast et al , 2002. Metoclopramide is a D2 dopamine receptor antagonist, and additionally activates the serotonin 5HT 4 receptor.…”

Section: Discussionmentioning

confidence: 99%

Lack of interaction between metoclopramide and morphinein vitroand in mice

et al. 2008

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1. This study examined interactions via common metabolism or via common pharmacodynamic pathways between frequently co-prescribed metoclopramide (a prokinetic) and morphine (an opioid analgesic). 2. In human liver microsomes, morphine 3-glucuronide and morphine 6-glucuronide formation had V(max) estimates of 6.2 +/- 0.07 and 0.75 +/- 0.01 (nmole min(-1) mg(-1) protein) and K(m) estimates of 1080 +/- 37 and 665 +/- 55 (microM), respectively. The in vitro K(i) for morphine 3-glucuronide formation in the presence of metoclopramide in human liver microsomes or recombinant uridine diphosphoglucuronosyltransferase 2B7 predicted a lack of in vivo interaction. 3. Morphine (2 mg kg(-1) subcutaneously) delayed gastrointestinal meal transit in mice, metoclopramide (10 mg kg(-1) subcutaneously) had no effect on meal transit, and metoclopramide did not alter this effect of morphine. 4. Morphine (2 or 5 mg kg(-1) subcutaneously) was antinociceptive in mice (hot plate test) and metoclopramide (10 mg kg(-1) subcutaneously) did not alter the antinociceptive effects of morphine. 5. Together, the data suggest a lack of interaction between morphine and metoclopramide.

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“…These effects of morphine that are named state-dependent learning have been demonstrated previously [3,4,29,30] . Moreover, it has been shown that repeated administration of morphine may induce tolerance to its own response [31] . However, repeated administration of morphine followed by a period of drugfree treatment might induce sensitization [32][33][34] .…”

Section: Discussionmentioning

confidence: 99%

Morphine State-Dependent Learning Sensitization and Interaction with Nitric Oxide

et al. 2006

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In the present study, the effects of nitric oxide (NO) precursor L-arginine and L-NAME, a potent inhibitor of NO synthase (NOS), on the expression of sensitization of morphine were investigated. Pre-training administration of morphine (5 mg/kg) impaired memory retrieval compared to pre-training saline-treated animals. Amnesia due to pre-training morphine (5 mg/kg) was restored by pre-test morphine (5 mg/kg).The retrieval impairment was also inhibited in mice which had received once-daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days, followed by 5 days of no drug treatment before training (in order to induce morphine sensitization). Administration of L-arginine (60 mg/kg/day – 3 days) or L-NAME (20 mg/kg/day – 3 days) before training did not alter morphine state dependency. During acquisition of sensitization, administration of L-arginine (60 mg/kg) 20 min before morphine (10 mg/kg/day, for 3 days) increased, while injection of L-NAME (20 mg/kg) 20 min before morphine (30 mg/kg/day, for 3 days) decreased morphine state dependency. It is concluded that NO is involved in the morphine-induced sensitization.

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Dopamine receptor mechanism(s) and morphine tolerance in mice

Cited by 47 publications

References 46 publications

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord

Lack of interaction between metoclopramide and morphinein vitroand in mice

Morphine State-Dependent Learning Sensitization and Interaction with Nitric Oxide

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