Research reportBrain opioid receptor adaptation and expression after prenatal exposure to buprenorphine
Introduction
Buprenorphine, an oripavine alkaloid derivative, is currently marketed as an analgesic agent and is undergoing clinical evaluation for the treatment of heroin addiction in the United States. In countries such as France and Israel, it has been approved for use in opiate addiction rehabilitation. Acute and chronic administration of buprenorphine can attenuate or even block the effects of opioid agonists, including morphine, heroin and hydromorphone in humans 7, 26, 38, 40. This mixed agonist–antagonist displays fewer adverse side effects and less abuse potential than other opioid agonists used in drug rehabilitation [18]. Two promising approaches have been studied recently, the use of a combination of buprenorphine and the opioid antagonist naloxone in opiate-dependent users 21, 27or the substitution of buprenorphine for methadone 23, 32, 35. Nevertheless, little is known about the effects of mixed agonist–antagonists such as buprenorphine on opioid receptor adaptation and expression, especially during early brain development. This information would have implications for the adoption of buprenorphine in the treatment of maternal drug abuse, since opioid binding sites in developing brain are particularly susceptible to opiate exposure 22, 36.
Pathological manifestations of prenatal opioid exposure including physiological and psychological delays have been described [22]. Opioid receptors in developing brain readily undergo adaptation upon opiate exposure. The advantages of buprenorphine over methadone include: a longer lasting action and thus, use on an alternate-day schedule; less physical dependence; a lower risk of overdose and a less intense withdrawal state 25, 41. Hence, the in utero actions of the drug have ramifications for its adoption in rehabilitation of maternal drug abuse and its pre- and postnatal effects should be assessed in a developing animal model system.
Surprisingly, little data are available on the physiological consequences of prenatal buprenorphine exposure. Early biochemical studies suggested that in utero buprenorphine exposure did not alter met- or leu-enkephalin levels in rodents 28, 29, 39. Consistent with the down-regulation of μ receptors of both adult and P7 rats by this drug [5], administration of 0.5 mg/kg buprenorphine to pregnant rats caused μ receptor down-regulation in brain membranes of their P1 offspring [4]. Data on possible behavioral effects associated with prenatal buprenorphine exposure are also limited. Prenatal buprenorphine exposure does not alter activity or developmental milestones 28, 29, although there is one conflicting report [31]. These findings are in contrast with effects of prenatal methadone exposure on activity and developmental milestones 13, 42, 43. Similarly, rest-activity cycles were disrupted by prenatal methadone exposure [17]but not prenatal buprenorphine exposure [16]. Prenatal buprenorphine exposure does appear to alter sexually dimorphic nonreproductive behaviors including saccharin preference and juvenile spontaneous parental behaviors [1]. Because of interest in its adoption for treatment of opiate addiction, further research on in utero effects of buprenorphine on opioid receptor expression and adaptation is warranted. Here, we report on μ and κ opioid binding in brain membrane preparations from P1 rats after gestational buprenorphine treatment of their mothers. To assess prenatal effects of buprenorphine on brain opioid receptors, pregnant rats were administered three doses of buprenorphine (0.3, 0.6 or 2.5 mg/kg) and levels of P1 pup brain μ and κ opioid sites were estimated by binding and cross-linking assays. In addition, we evaluated the gestational effects of buprenorphine on opioid receptor expression by measuring μ and κ mRNA levels in P1 brain extracts by RT-PCR.
Section snippets
Chemicals
[d-Ala2,mephe4,gly-ol5] enkephalin (DAMGE), (37 Ci/mmol), β-endorphin, (2000 Ci/mmol) were obtained from Multiple Peptide Systems (San Diego, CA); buprenorphine and U69593 were from NIDA Drug Supply (Research Triangle, NC). (56 Ci/mmol) was from Amersham (Arlington Heights, IL). The following were obtained from the indicated sources: Ultraspec™ RNA isolation solution (Biotecx, Houston, TX); RNEasy™ total RNA preparation kit (Qiagen, Chatsworth, CA);
Opioid binding parameters of brain membrane preparations from P1 rats prenatally exposed to 2.5 mg/kg buprenorphine
A significant down-regulation of μ-opioid binding in P1 brain membranes was induced by in utero buprenorphine (0.5 mg/kg) treatment [4]. However, changes in κ binding were not detected under the same conditions. In the present studies the concentration of buprenorphine was elevated to 2.5 mg/kg and both (μ) and (κ) binding parameters (Bmax and Kd values) were measured in P1 brain membranes. Buprenorphine exposure reduced μ binding density by 78% in brains of P1 pups without
Discussion
In the present study, we show that in utero exposure to buprenorphine results in up-regulation of κ1 receptors as well as down-regulation of μ opioid receptors in P1 pup brains. Up-regulation of κ1 opioid binding required higher doses of buprenorphine than did down-regulation of μ receptors, as seen previously for both adult and P7 rats. Also consistent with previous investigations, binding affinities were unaffected by buprenorphine treatment under conditions in which brains were harvested
Acknowledgements
This work was supported by NIH grants DA05412 (CJC), HL5T32 H207050 (LMB) and NRCIA DA05766 (LMB). We thank Matt Mabery for assistance in densitometric analysis.
References (44)
- et al.
Prenatal buprenorphine exposure and sexually dimorphic nonreproductive behaviors in rats
Pharmacol. Biochem. Behav.
(1997) - et al.
Transient down-regulation of neonatal rat brain μ-opioid receptors upon in utero exposure to buprenorphine
Dev. Brain Res.
(1994) - et al.
CNS levels of mu opioid receptor (MOR-1) mRNA during chronic treatment with morphine or naltrexone
Brain Res. Bull.
(1995) - et al.
The effect of prenatal methadone exposure on development and nociception during the early postnatal period of the rat
Neurotoxicol. Teratol.
(1991) - et al.
Covalent labeling of opioid receptors with radioiodinated human β-endorphin
J. Biol. Chem.
(1985) - et al.
Prenatal administration of buprenorphine in the rat: effects on the rest-activity cycle at 22 and 30 days of age
Pharmacol. Biochem. Behav.
(1996) - et al.
Agonist regulation of the expression of the delta opioid receptor in NG108-15 cells
FEBS Letters
(1995) - et al.
Opioid antagonist challenges in buprenorphine maintained patients
Drug Alcohol Depend
(1990) - et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951) - et al.
Ligand: a versatile computerized approach for characterization of ligand-binding systems
Anal. Biochem.
(1980)
In vivo homologous regulation of mu-opioid receptor gene expression in the mouse
Eur. J. Pharmacol.
Antagonist-induced opiate receptor upregulation in cultures of fetal mouse spinal cord-ganglion explants
Dev. Brain Res.
Effects of exposure in utero to methadone and buprenorphine on enkephalin levels in the developing rat brain
Neurosci. Lett.
Pharmacotherapy for opioid and cocaine abuse
Med. Clin. N. Am.
Development of motor activity in young rats following methadone exposure
Pharmacol. Biochem. Behav.
Comparison of the butyrate effects on neurotransmitter receptors in neurohybrids NG108-15 and NCB-20 cells
Life Sci.
Buprenorphine differentially alters opioid receptor adaptation in rat brain regions
J. Pharmacol. Exp. Ther.
Agonist-induced desensitization and down-regulation of δ opioid receptors alter the levels of their cross-linked products in subcellular fractions from NG108-15 cells
Biochemistry
Differential down- and up-regulation of rat brain opioid receptor types and subtypes by buprenorphine
Mol. Pharmacol.
Up-regulation of δ opioid receptors in neuroblastoma hybrid cells; evidence for differences in the mechanisms of action of sodium butyrate and naltrexone
J. Pharmacol. Exp. Ther.
A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts
Clin. Pharmacol. Ther.
Evidence for κ and μ opioid receptor expression in c6 glioma cells
J. Neurochem.
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