Kinetics of drug action in disease states. XLI. Effect of adrenalectomy on the hypnotic activity of phenobarbital, the neurotoxicity of theophylline and pain sensitivity in rats.

The purpose of this investigation was to determine the effects of adrenalectomy and adrenalectomy with corticosterone replacement on pain sensitivity and on the pharmacodynamics of a central nervous system depressant, phenobarbital, and a central nervous system stimulant, theophylline. Male Sprague-Dawley rats, bilaterally adrenalectomized, were maintained on normal saline solution or normal saline solution with corticosterone, 160 micrograms/ml, as drinking water for 9 or 11 days. Sham-operated animals served as normal controls. They were then tested for pain sensitivity by the tail-flick method. Phenobarbital or theophylline was infused i.v. slowly until the onset of loss of righting reflex or of maximal seizures, respectively. Samples of cerebrospinal fluid (CSF), blood (for serum) and the brain were obtained at that time and assayed for phenobarbital or theophylline by high-performance liquid chromatography. Compared to the controls, the adrenalectomized rats required a smaller dose and lower concentrations of phenobarbital in serum, brain and CSF (12% decrease) to produce loss of righting reflex. The opposite effect was observed in adrenalectomized rats supplemented with corticosterone. Adrenalectomy had no apparent effect on the dose and the serum, brain and CSF concentrations of theophylline at the onset of maximal seizures whereas adrenalectomized, corticosterone-supplemented animals required a larger dose and higher concentrations (17% increase in CSF) of theophylline than controls to produce seizures. Tail-flick latency was slightly (19%) but statistically significantly reduced in adrenalectomized rats and lengthened (18%) in adrenalectomized, corticosterone-supplemented animals.