Research report
Visualization of μ opiate receptor downregulation following morphine treatment in neonatal rat brain

https://doi.org/10.1016/0165-3806(91)90204-VGet rights and content

Abstract

In order to visualize neuroanatomical alterations in specific brain regions, light microscopy autoradiography was carried out on neonatal brain sections from controls and neonates chronically treated with morphine. In the case of brains exposed to morphine from postnatal day (PD) 1–4, μ receptor density on PD 5 was non-existent in the patches of the striatum. There were also decreases in μ opiate receptor density in the surrounding matrix area, and in the nucleus accumbens and amygdala. Longer durations of morphine treatment (PD 1–8) did not show these alterations in μ opiate receptor density. These data demonstrate the unique plasticity seen in the immature opioid system. It is suggested that the differences observed in neonatal vs adult central nervous system may be due to interactions with and the differential development of the G-protein/cyclic adenosine 3′,5′-monophosphate (cAMP) system.

References (48)

  • B.J. Morris et al.

    Control of opiate receptor number in vivo: simultaneous kappa-receptor down-regulation and mu-receptor up-regulation following chronic agonists/antagonist treatment

    Neuroscience

    (1989)
  • P. Petrillo et al.

    Differential postnatal development of mu-, delta-, and kappa-opioid binding sites in rat brain

    Brain Res.

    (1987)
  • B.L. Roth et al.

    The effects of morphine on catecholamine metabolism during postnatal development

    Brain Res.

    (1980)
  • K.F. Shen et al.

    Cholera toxin-A subunit blocks opioid excitatory effects on sensory neuron action potentials indicating mediation by Gs-linked opioid receptors

    Brain Res.

    (1990)
  • K.F. Shen et al.

    Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture

    Brain Res.

    (1989)
  • T.A. Slotkin et al.

    Maternal methadone administration: deficient in development of alpha-nor-adrenergic responses in developing rat brain as assessed by norepinephrine stimulation of 33Pi incorporation into phospholipids in vivo

    Biochem. Pharmacol.

    (1982)
  • A. Tavani et al.

    Differential postnatal development of mu, delta, and kappa opioid binding sites in mouse brain

    Dev. Brain Res.

    (1985)
  • A. Tempel et al.

    Morphine-induced downregulation of μ-opioid receptors in neonatal rat brain

    Dev. Brain Res.

    (1988)
  • D. Tsang et al.

    Effect of antenatal exposure to opiates on the development of opiate receptors in rat brain

    Brain Res.

    (1980)
  • J.R. Unnerstall et al.

    Ontogeny of opiate binding sites in the hippocampus, olfactory bulb and other regions of the rat forebrain by autoradiographic methods

    Dev. Brain Res.

    (1983)
  • B.H.C. Westerink

    Further studies on the sequence of dopamine metabolism in the rat brain

    Eur. J. Pharmacol.

    (1979)
  • S. Algeri et al.

    Effects of enkephalins on catecholamine metabolism in rat CNS

  • B. Attali et al.

    Long-term opiate exposure leads to reduction of the αi-1 subunit of GTP-binding proteins

    J. Neurochem.

    (1989)
  • A. Bloom et al.

    The correlation between antinociceptive activity of narcotics and their antagonists as measured in the mouse tail-flick test and increased synthesis of brain catecholamines

    J. Pharmacol. Exp. Ther.

    (1976)
  • Cited by (39)

    • Surgery, Anesthesia, and the Immature Brain

      2019, A Practice of Anesthesia for Infants and Children
    • Surgery, Anesthesia, and the Immature Brain

      2018, A Practice of Anesthesia for Infants and Children
    • Neurodevelopmental implications of the use of sedation and analgesia in neonates

      2013, Clinics in Perinatology
      Citation Excerpt :

      Opioids have been shown to have many different effects at a cellular level. Perinatal morphine causes altered dendritic architecture and neuronal density49 and reduces μ-receptor density.50 Perinatal administration of either methadone or buprenorphine reduces the content of the neurotrophic factor nerve growth factor.51

    • The impact of the perioperative period on neurocognitive development, with a focus on pharmacological concerns

      2010, Best Practice and Research: Clinical Anaesthesiology
      Citation Excerpt :

      Some studies even suggested that opioid co-administration can enhance cell death of immature brain cells induced by other compounds.44 Chronic perinatal exposure to morphine, fentanyl or methadone has been shown to induce acute neuronal degeneration in the neonatal brain45, to alter brain opioid-receptor density46–48 and to disrupt nerve growth factor expression as well as dopaminergic, noradrenergic, serotonergic and cholinergic activity.49,50 Moreover, perinatal opioid administration can cause long-lasting desensitisation to opioid analgesia in adult animals51 and has also been shown to induce long-term behavioural changes, cognitive deficits and learning impairment extending into adulthood.52–57

    • Advancement of reproductive senescence and changes in the early expression of estrogen, progesterone and μ-opioid receptors induced by neonatal hypoxia in the female rat

      2008, Brain Research
      Citation Excerpt :

      It has been shown that hypoxia induces increases of endogenous opioids (Wardlaw et al., 1981), that could lead to a homologous down regulation of these abundant receptors in the perinatal brain that may last several days. Since the present data showed a marked decrease in µOR expression from female rats submitted to hypoxia on postnatal day 7, it is also possible that the endogenous opioids released by the H or HI may mediate the decrease of µOR through a process of downregulation, as has been seen in rat brains exposed to exogenous opiates in the early postnatal intervals (Tempel, 1991). Interestingly, steroid receptors are also targets of neonatal endorphin imprinting (Csaba and Karabelyos, 2001); and the expression of ER α and β has been reported to be affected in vitro by oxidative stress, that is a key component in the unfolding of the effects of an hypoxic episode (Tamir et al., 2002).

    View all citing articles on Scopus
    View full text