Down-regulation of central receptors for thyrotropin-releasing hormone in kappa opiate agonist-induced abstinence in the rat.
1992
Abstract The effect of U-50,488H, a selective kappa opiate agonist, on tolerance-dependence and abstinence on the TRH receptors of the spinal cord and discrete regions of the brain of male Sprague-Dawley rats was determined. Rats were injected intraperitoneally twice daily with 25 mg/kg of U-50,488H for 4 days. Rats serving as controls were injected with the vehicle. On day 5, rats which were labeled as tolerant to U-50,488H were injected with U-50,488H (25 mg/kg) and sacrificed 1 hr later, whereas those labeled as abstinent were sacrificed without any injection. The above procedure has been previously shown to produce a high degree of tolerance to the analgesic and hypothermie effects of U-50,488H. The spinal cord and regions of the brain (hippocampus, cortex, midbrain, hypothalamus, corpus striatum, pons and medulla, and amygdala) were isolated for binding studies. The ligand [ 3 H]MeTRH was used for TRH receptors. The binding constants, B max and K d values, of [ 3 H]MeTRH to bind to membranes prepared from various regions of the brain and spinal cord of rats tolerant-dependent on U-50,488H were unaffected. However, in rats abstinent to U-50,488H, the binding of [ 3 H]MeTRH to membranes of the hypothalamus, and pons and medulla, was decreased. The decreased binding of [ 3 H]MeTRH to hypothalamic membranes was due to changes in B max value, while in pons and medulla it was due to an increase in the K d value. The results suggest that the development of tolerance to the pharmacological effects of U-50,488H does not alter central TRH receptors but abstinence from U-50,488H is associated with down-regulation of TRH in specific sites in the brain, namely hypothalamus, and pons and medulla. The results provide further evidence for an interaction between kappa opiates and TRH receptors
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