Paradoxical Modulation of Nociception in Mice by Barbiturate Agonism and Antagonism: Is a GABA Site Involved in Nociception?

Carmody J, Knodler L, Murray S.

School of Physiology and Pharmacology, University of New South Wales, Kensington (Sydney), NSW 2033, Australia.

In a battery of four acute and chronic nociceptive tests, the GABA antagonist picrotoxin produces a uniform and sustained analgesia in mice. By contrast, barbiturates which have been presumed to act at the same receptor produce mixed and paradoxical actions. At a standard time of 10 min after drug administration a convulsant barbiturate [5-ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid] produced analgesia in three tests but had no effect in the fourth; a pure hypnotic barbiturate (amylobarbitone) produced hyperalgesia in three tests but analgesia in the fourth; while the mixed hypnotic-convulsant pentobarbitone produced hyperalgesia in two of the tests and was without any effect in the other two. There was no pattern in these results with respect to acute or chronic nociceptive tests. Surprisingly, with extended observation using the tail-flick test both pentobarbitone and the pure hypnotic (amylobarbitone) gave early hyperalgesia followed by analgesia; the convulsant barbiturate gave only analgesia. The results suggest a role for GABAA receptors in the transmission of nociceptive information; they also suggest that barbiturates act at quite a different receptor.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12106449&dopt=Abstract barbiturate Butalbital Fioricet





Effect of dexamethasone, barbiturate and hypothermy on edema induced by CO2 laser brain lesion in the dog: light and electron microscopic study.

Gocer AI, Ildan F, Polat S, Bagdatoglu H, Tunah N, Kaya M, Haciyakupoglu S.

Department of Neurosurgery, Cukurova University School of Medicine, Balcale, Adana, Turkey.

Experiments were carried out to compare the effectiveness of dexamethasone, a barbiturate, and hypothermy on experimental cerebral edema caused by CO2 laser in dogs. Experimental brain lesions were created over the right frontal cortex of the dogs through the intact dura mater with CO2 laser energy (40 W impact, 0.5 second duration, for a total time of 4 seconds on a 12.5 mm surface). Animals were divided into four groups and treated with dexamethasone, a barbiturate, hypothermy, and a crystalloid (control group). The brains were examined 48 hours after injury. Histologically all brain lesions showed three distinct layers with a vaporized center bordered by a zone of coagulation necrosis surrounded by edema. The main finding in the surrounding coagulation and edematous layers was dilatation of the vessels. Hemorrhage was sometimes observed mainly in the edematous layer. The effect of these therapies on the laser lesion and the effectiveness of these therapies on surrounding cerebral edema were evaluated by both light and electron microscopy. The control group showed significantly greater edema than the dexamethasone group. There was only a minimal difference between the control group and the barbiturate group, and there was no significant difference in amount of edema between control group and the hypothermy group. There was less edema in the dexamethasone group than in the other ones. These data suggest that dexamethasone inhibits edema in CO2 laser lesions with the same efficacy as shown in the treatment of vasogenic edema.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8738363&dopt=Abstract barbiturate Butalbital Fioricet





Inhibitory effects of intravenous anaesthetic agents on K(+)-evoked glutamate release from rat cerebrocortical slices. Involvement of voltage-sensitive Ca(2+) channels and GABA(A) receptors.

Kitayama M, Hirota K, Kudo M, Kudo T, Ishihara H, Matsuki A.

Department of Anesthesiology, University of Hirosaki, School of Medicine, Hirosaki 036-8563, Japan.

It is widely accepted that most general anaesthetic agents depress the central nervous system (CNS) by potentiation or activation of the GABA(A) receptor-mediated Cl(-) conductance. These agents also reportedly inhibit voltage-sensitive Ca(2+) channels (VSCCs), thus depressing excitatory transmission in the CNS. However, in this regard there are few functional data at the level of neurotransmitter release. In this study we examined the effects of VSCC antagonists and a range of intravenous anaesthetic agents on K(+)(40 mM)-evoked glutamate release from rat cerebrocortical slices in the absence and presence of the GABA(A) receptor antagonist bicuculline (100 microM). We employed both selective and non-selective VSCC antagonists, the anaesthetic barbiturates thiopental, pentobarbital and phenobarbital, the non-anaesthetic barbiturate barbituric acid, the non-barbiturate anaesthetics alphaxalone, propofol and ketamine and the GABA(A) receptor agonist, muscimol. Glutamate released into the incubation medium was determined by a glutamate dehydrogenase-coupled assay. Omega-agatoxin IV(A) (P-type VSCC), omega-conotoxin MVII(C) (P/Q-type VSCC) and Cd(2+) (non-selective) essentially abolished glutamate release whilst nifedipine (L-type VSCC) and omega-conotoxin GVI(A) (N-type VSCC) reduced release by less than 30%. The concentrations producing 50% of the maximum inhibition (IC(50)) for thiopental, pentobarbital, phenobarbital, alphaxalone, propofol and ketamine were (in microM) 8.3, 22, 112, 6.3, 83 and 120, respectively. Barbituric acid produced a small (about 20%) inhibition. With the exception of ketamine, the IC(50) values for these anaesthetic agents were increased threefold by bicuculline (100 microM). In addition, muscimol significantly inhibited release by 26% with an IC(50) of 1.1 microM. In summary, a range of anaesthetic agents at clinically achievable concentrations inhibit glutamate release and this inhibition of release appears to be due mainly to direct inhibition of P/Q-type VSCCs, although activation of the GABA(A) receptor plays a role in this response.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12172707&dopt=Abstract barbiturate Butalbital Fioricet





Effects of combining midazolam and barbiturate on the response to tracheal intubation: changes in autonomic nervous system.

Nishiyama T, Misawa K, Yokoyama T, Hanaoka K.

Surgical Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. nishiyam ims.u-tokyo.ac.jp.

STUDY OBJECTIVE: To investigate the effects on the autonomic nervous system of anesthesia induction with a combination of midazolam and barbiturate using plasma catecholamine concentration and heart rate (HR) variability in comparison with the induction with barbiturate alone. DESIGN: Prospective study. SETTING: Operating room of a university hospital. PATIENTS: 40 ASA physical status I and II patients aged 30 to 70 years, who were scheduled for general anesthesia. INTERVENTIONS: Anesthesia was induced with 0.1 mg/kg midazolam followed by 3 mg/kg thiopental sodium (Midazolam-Barbiturate group) or thiopental 5 mg/kg (Barbiturate group) with 6 L/min oxygen. MEASUREMENTS: Arterial blood pressure (BP), HR, HR variability, and plasma concentrations of epinephrine and norepinephrine were measured. MAIN RESULTS: Blood pressure and HR increased in response to tracheal intubation in both groups, but the increase was significantly larger in the Barbiturate group. In the Barbiturate group, the high-frequency component (HF) in HR variability increased significantly during intubation, whereas in the Midazolam-Barbiturate group, HF decreased continuously. The low-frequency component (LF)/HF ratio increased in both groups, with significantly higher values noted in the Barbiturate group. Plasma epinephrine concentrations decreased before intubation and increased in response to tracheal intubation in the Barbiturate group. Finally, plasma norepinephrine concentrations increased in response to tracheal intubation only in the Barbiturate group. CONCLUSIONS: Anesthesia induction with a combination of midazolam-thiopental was effective in reducing hemodynamic and cardiac autonomic nervous system responses to tracheal intubation in comparison with the conventional induction with thiopental alone.

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