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Is GABA involved in analgesia?
Abstract
The effect of morphine and naloxone on gamma-aminobutyric acid (GABA) concentration in discrete areas of the rat brain has been studied. Neither morphine nor naloxone had a significant effect on regional steady-state concentrations of GABA. The results have been discussed with respect to the role of GABA in pain and analgesia.
The kinetic constants for 4-aminobutyrate: 2-oxoglutarate aminotransferase (GABA-trans-aminase) and succinate-semialdehyde: NAD+ oxidoreductase (SSA-DH) have been determined using rat brain homogenate.
The Michaelis constants for GABA-T at saturated substrate concentrations were calculated to be Kgaba= 1.5 mM, K2-OG= 0.25 mM, KGLU= 620 μM, and KSSA= 87 μm. The Vmax for the reaction using GABA and 2-oxoglutarate (2-OG) as substrates (forward reaction) was found to be 35.2 μmol/ These results indicate that MOPEG is a measure for changes in central noradrenaline turnover and that drugs affect MOPEG in the brain and spinal cord similarly. Fractional rate constants of MOPEG in the rat brain and spinal cord were estimated with the exponential decline curves produced by treatment with pargyline. Turnover rates of 193 pmol/gh and 167 pmol/g These results indicate that MOPEG is a measure for changes in central noradrenaline turnover and that drugs affect MOPEG in the brain and spinal cord similarly. Fractional rate constants of MOPEG in the rat brain and spinal cord were estimated with the exponential decline curves produced by treatment with pargyline. Turnover rates of 193 pmol/g/h and 167 pmol/g/h in the brain and spinal cord respectively were calculated.
The kinetics of GABA-T have been shown to be consistent with a Ping Pong Bi Bi mechanism. Substrate inhibition of the forward reaction, through formation of a dead-end complex, was found to occur with 2-OG (Ki 3.3 mM), whereas GABA was found to be a product inhibitor of the reverse reaction (Ki= 0.6 mM). Using the appropriate Haldane relationship, a Keq of 0.04 for GGBA-T was found, indicating that the reaction was strongly biased towards GABA.
For SSA-DH, the Km of SSA was determined (9.1 μM) and the Vmax was 27.5 μmol/ These results indicate that MOPEG is a measure for changes in central noradrenaline turnover and that drugs affect MOPEG in the brain and spinal cord similarly. Fractional rate constants of MOPEG in the rat brain and spinal cord were estimated with the exponential decline curves produced by treatment with pargyline. Turnover rates of 193 pmol/g/h and 167 pmol/g These results indicate that MOPEG is a measure for changes in central noradrenaline turnover and that drugs affect MOPEG in the brain and spinal cord similarly. Fractional rate constants of MOPEG in the rat brain and spinal cord were estimated with the exponential decline curves produced by treatment with pargyline. Turnover rates of 193 pmol/g/h and 167 pmol/g/h in the brain and spinal cord respectively were calculated. h. The effect of di-n-propylacetate (DPA) on both GABA-T and SSA-DH was measured. DPA inhibited SSA-DH competitively with respect to SSA, giving a Ki of 0.5 mM. GABA-T was only slightly inhibited. The Ki of DPA for the forward reaction was 23.2 mM with respect to GABA, which was 40-50 times higher than that for SSA-DH. For the reverse reaction the Ki of DPA was found to be nearly the same (15.2 mM with respect to Glu and 22.9 mM with respect to SSA). These results suggest that GABA accumulation in the brain, after administration of DPA in vivo, is caused by SSA-DH inhibition. Two mechanisms are indicated by the data. (1) The higher level of SSA, which results from inhibition of SSA-DH, initiates the reverse reaction of GABA-T, thus increasing the level of GABA via conversion of SSA. (2) The degradation of GABA is inhibited by SSA, since SSA has a strong inhibitory effect on the forward reaction, as calculated from the present data.
Quasi-morphine abstinence behaviour induced by di-n-propylacetate (DPA) in rats is thought to be caused by an increased GABAergic activity in the CNS. Behavioural responses after intracerebral injections of DPA were studied to gain insight into the centre median-parafascicularis (Cm-Pf) resulted in a large number of body shakes and greater locomotor activity when compared to other brain areas. Injection of DPA into the central amygdala (Ac) resulted in an enhanced number of chewing episodes. Administration of bicuculline methiodide (BMI) into the Cm-Pf, 5 min after intraperitoneal administration of DPA, suppressed by body shakes but had only minor effects on horizontal activity, whereas injection of morphine into the same structure suppressed both behavioural symptoms. It is concluded that GABAergic and opioid mechanisms in the Cm-Pf are involved in the DPA-induced behaviour. Injection of BMI into the central amygdala shortly after i.p. injection of DPA resulted in an increase in the number of body shakes, whereas no effect was observed on activity. Morphine applied to this structure slightly potentiated the locomotor activity, but had no effect on the body shakes induced by DPA. The present results suggest a facilitatory role for a GABAergic system in the Cm-Pf on body shakes, while in the central amygdala a GABAergic system exerts an inhibitory influence on this symptom of abstinence.
The role of the noradrenergic system in quasi-morphine abstinence behaviour induced by di-n-propylacetate (DPA) in rats has been studied. Depletion of noradrenaline (NA), by treatment with FLA-63, decreased the number of body shakes and the extent of horizontal activity evoked by DPA. Almost total suppression of these symptoms was obtained by injection of 20 ng morphine bilaterally into the locus coeruleus (LC). Destruction of the LC system by electrolytic lesion of the LC or by injection of 6-hyrodroxy-dopamine into the dorsal bundle revealed that degeneration of the NA system by at least 80% appears to be necessary to decrease the number of body shakes. It is concluded that the noradrenergic LC system fulfills a modulatory role in quasi-morphine abstinence behaviour induced by DPA.
THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridone-3-ol), a direct acting GABA receptor agonist, has been shown to have antinociceptive properties. To determine whether tolerance develops to the analgesic response, mice received multiple injections of THIP for up to 21 days after which analgesia was tested using both tail immersion and hot-plate methods. Both tests indicated a significant reduction in the antinociceptive response to THIP, as well as other GABA agonists, beginning between days 3 and 5 of chronic administration. Moreover, these animals demonstrated a decreased analgesic response to morphine, and morphine tolerant animals were also less responsive to THIP. These data indicate that opiates and GABA agonists induce analgesia by acting through separate but related pathways in the central nervous system.
The irreversible inhibitors of GABA-transaminase, γ-acetylenic GABA and γ-vinyl GABA, were examined for antinociceptive actions in rodents. An antinociceptive effect unaccompanied by ataxia was demonstrated in mice on the 52°C hot-plate and in rats in a tail-stimulation procedure and was maximal at 4–6 hr after drug administration, which correlates temporally with reported maximal increases of brain GABA. The antinociceptive effect was antagonized by a subconvulsive dose of bicuculine (0.5 mg/kg, i.p.) in rats, but could not be prevented by naloxone (1 mg/kg, i.p.) in mice. Only the (+)-stereoisomer γ-vinyl GABA, active as a GABA-transaminase inhibitor, was antinociceptive. The effects appear to be causally related to elevated cerebral GABA levels. The profile of these agents in the tail stimulation test in rats suggests a specific antinociceptive effect since vocalization and vocalization after-discharge were similarly affected. The analgesic actions of morphine in mice on the 56°C hot-plate were enhanced 5 hr after the administration of γ-acetylenic GABA or γ-vinyl GABA. The compounds did not alter the naloxone-precipitated morphine withdrawal syndrome in the rat.It is concluded that γ-acetylenic GABA and γ-vinyl GABA can produce distinct antinociceptive effects in rats and mice related to increased brain GABA levels, but which are not opioid-like in nature.
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