Correlation between the increased release of catecholamines evoked by local anesthetics and their analgesic and adverse effects: Role of K + channel inhibition

Abstract

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.

Effects of chlorogenic acid on voltage-gated potassium channels of trigeminal ganglion neurons in an inflammatory environment

“…The results of our studies also supported that conclusion, we found that CGA inhibited the effects of PGE 2 on K V channels, that is, CGA may act on K V channels to alleviate inflammatory pain. In addition, Sircuta et al have found that inhibition of potassium (K + ) channels by potassium channel inhibitor 4-AP could increase the resting-and action potentialevoked release of [ 3 H]dopamine ([ 3 H]DA) and [ 3 H]noradrenaline ([ 3 H]NA) from rat prefrontal cortex and spinal cord slices (Sircuta et al, 2016). And our results demonstrated that CGA could inhibit the peak current density of I K,A activation.…”

Effect of rat spinal cord injury (hemisection) on the ex vivo uptake and release of [ 3 H]noradrenaline from a slice preparation

“…This study is the first to reveal the modulation of NA release from the decentralised nerve terminals of noradrenergic nerves by unilateral hemisection of the spinal cord in adult rats. The experiments in the present study were performed to determine whether an artificially induced spinal cord injury had similar effects on noradrenaline uptake and release as the simulation of ischaemic conditions in healthy tissues in vitro (Uchihashi et al, 1998;Nakai et al, 1999;Sumiya et al, 2001;Sircuta et al, 2016) and in vivo (Globus et al, 1989). In contrast to the above-mentioned studies, normal Krebs perfusion solution was used in the present study, but the spinal cord tissue was isolated caudally and in close proximity (2-5 mm) to an artificial injury (Schoultz and DeLuca, 1974).…”

Administrations of thalidomide into the rostral ventromedial medulla alleviates painful diabetic neuropathy in Zucker diabetic fatty rats

“…Previous studies have shown that systemic or intrathecal stimulation of inhibitory dopamine D2 receptors results in inhibition of cold and tactile allodynic responses (Cobacho et al, 2014). Furthermore, inhibition of local catecholamine release in the spinal cord may contribute to neuropathic pain relief and spinal analgesia (Sircuta et al, 2016). While no studies have examined the role of catecholamine neurotransmissions in the RVM in diabetic neuropathy, it has been shown that thalidomide can increase striatal dopamine release in laboratory animals (Boireau et al, 1997;Narita et al, 2002).…”