The influence of cryogenic brain injury on the pharmacodynamics of pentobarbital. Evidence for a serotonergic mechanism.
To study of the influence of brain injury on the pharmacodynamics of pentobarbital, the authors examined the effect of a focal cortical freezing lesion in rats on the brain concentration of pentobarbital associated with lack of response to tail clamp. The freezing lesion was made with a probe (-50 degrees C) applied through a craniotomy to the intact dura over the left parietal cortex. Three days after injury the rats were anesthetized with a continuous intravenous infusion of pentobarbital until they first did not respond to tail clamp stimulation. The brains were then removed for determination of pentobarbital by high-performance liquid chromatography. The brain pentobarbital concentration required to prevent response to tail clamp (EC50) was reduced from 209 +/- 39 nmol/g (mean +/- standard deviation) in rats without brain injury to 149 +/- 28 nmol/g in the injured animals (P = 0.005). The cortical serotonin (5-HT) concentration was increased from 1904 +/- 358 pmol/g in uninjured rats to 2513 +/- 598 pmol/g (P less than 0.01) in injured animals ipsilateral to the lesion. Pretreatment of the rats with p-chlorophenylalanine (PCPA, 200 mg/kg by intraperitoneal injection) to inhibit 5-HT synthesis abolished both the increase in 5-HT concentration associated with the injury (left cortex, 708 +/- 389 pmol/g; right cortex, 911 +/- 979 pmol/g) and the effect of the lesion on EC50 (uninjured, EC50 = 186 +/- 24 nmol/g; injured, EC50 = 179 +/- 47 nmol/g). Prevention of the decrease in EC50 by inhibition of 5-HT synthesis provides support for a functional role for 5-HT in the influence of cold injury on the pharmacodynamics of pentobarbital.
Archer
D P
DP
Department of Anaesthesia, Foothills Hospital, Calgary, Alberta, Canada.
Priddy
R E
RE
Tang
T K
TK
Sabourin
M A
MA
Samanani
N
N
D000818:Animals; D001930:Brain Injuries / Q000503:physiopathology*; D010134:Fenclonine / Q000494:pharmacology; D005615:Freezing; D007262:Infusions, Intravenous; D008297:Male; D010424:Pentobarbital / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000096:biosynthesis* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology
D012702:Serotonin Antagonists; D012701:Serotonin; D010424:Pentobarbital; D010134:Fenclonine