Sim L J, Selley D E, Dworkin S I, Childers S R
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA.
J Neurosci. 1996 Apr 15;16(8):2684-92. doi: 10.1523/JNEUROSCI.16-08-02684.1996.
Chronic opiate administration results in the development of tolerance and dependence, but the regulation of mu opioid receptor function during this process is not clearly understood. To localize changes in mu opioid receptor-coupled G-protein activity in various brain regions after chronic morphine treatment, the present study examined mu opioid agonist-stimulated [35S]GTPgammaS binding to brain sections by in vitro autoradiography. Rats were treated for 12 d with increasing doses (10-320mg . kg-1 . d-1) of morphine. Control rats were injected with either saline or a single acute injection of morphine (20 mg/kg). mu opioid-stimulated [35S]GTPgammaS binding was measured by autoradiography of brain sections in the presence and absence of the mu opioid-selective agonist DAMGO. In rats injected with a single acute dose of morphine, no significant changes were detected in basal or agonist-stimulated [35S]GTPgammaS binding in any region. In sections from chronic morphine-treated rats, however, DAMGO-stimulated [35S]GTPgammaS binding was reduced significantly compared with control rats in the following brain-stem nuclei: dorsal raphe nucleus, locus coeruleus, lateral and medial parabrachial nuclei, and commissural nucleus tractus solitarius. No significant changes were observed in several other brain regions, including the nucleus accumbens, amygdala, thalamus, and substantia nigra. These data indicate that chronic morphine administration results in reductions in mu opioid activation of G-proteins in specific brainstem nuclei involved in physiological homeostasis and autonomic function, which may have implications in the development of opiate tolerance and physical dependence.
长期给予阿片类药物会导致耐受性和依赖性的产生，但在此过程中μ阿片受体功能的调节尚不清楚。为了定位慢性吗啡治疗后不同脑区中μ阿片受体偶联G蛋白活性的变化，本研究通过体外放射自显影检测了μ阿片激动剂刺激的[35S]GTPγS与脑切片的结合。大鼠连续12天接受递增剂量（10 - 320mg·kg-1·d-1）的吗啡治疗。对照大鼠注射生理盐水或单次急性注射吗啡（20mg/kg）。在存在和不存在μ阿片选择性激动剂DAMGO的情况下，通过脑切片的放射自显影测量μ阿片刺激的[35S]GTPγS结合。在单次急性注射吗啡的大鼠中，任何区域的基础或激动剂刺激的[35S]GTPγS结合均未检测到显著变化。然而，在慢性吗啡治疗大鼠的切片中，与对照大鼠相比，在以下脑干核中，DAMGO刺激的[35S]GTPγS结合显著降低：中缝背核、蓝斑核、外侧和内侧臂旁核以及孤束核连合核。在其他几个脑区，包括伏隔核、杏仁核、丘脑和黑质，未观察到显著变化。这些数据表明，长期给予吗啡会导致参与生理稳态和自主功能的特定脑干核中μ阿片对G蛋白的激活减少，这可能与阿片类药物耐受性和身体依赖性的发展有关。
