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Correlation between the increased release of catecholamines evoked by local anesthetics and their analgesic and adverse effects: Role of K(+) channel inhibition.
Brain Research Bulletin 2016 June
Because local anesthetics are known to inhibit both sodium and potassium channels, and anesthetic properties have been attributed to the former effect, we compared their effects with those of tetrodotoxin (TTX), a selective Na(+) channel inhibitor with anesthetic activity, and 4-aminopyridine (4-AP), a selective potassium channel blocker with convulsive activity, on transmitter release during rest and in response to field (axonal) stimulation using the microvolume perfusion method and isolated prefrontal cortex and spinal cord slice preparations loaded with the radioactive transmitters [(3)H]dopamine ([(3)H]DA) and [(3)H]noradrenaline ([(3)H]NA). It is also known that local anesthetics may exert analgesic effect and, rarely, some adverse effects on the central nervous system (CNS). Neurochemical evidence demonstrated that local anesthetics administered at concentrations ranging from 0.5 to 5mM, which might have been intentionally or accidentally achieved in clinical practice (e.g., during spinal and epidural anesthesia or peripheral nerve block), led to presynaptic failures during neurochemical transmission, including inhibited transmitter release associated with axonal firing and markedly enhanced extraneuronal concentrations of transmitters due to increased resting, [Ca(2+)]o-independent release. Tetrodotoxin, a toxin with selective Na(+) channel-blocking properties, inhibited the stimulation-evoked release but failed to affect the resting release. In contrast, the potassium channel inhibitor 4-AP enhanced both the resting- and action potential-evoked transmitter releases. It is concluded that effects of local anesthetics on resting catecholamine release in the spinal cord may contribute to their action during neuropathic pain relief and spinal analgesia as well as to their side effects in the CNS.
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