Amitriptyline inhibits striatal efflux of neurotransmitters via blockade of voltage-dependent Na+ channels

doi:10.1016/0014-2999(92)90726-K

European Journal of Pharmacology

Volume 221, Issues 2–3, 20 October 1992, Pages 377-380

https://doi.org/10.1016/0014-2999(92)90726-K Get rights and content

Abstract

Amitriptyline, a tricyclic antidepressant, almost completely inhibited veratridine- or scorpion toxin-evoked efflux of endogenous dopamine (DA) and γ-aminobutyric acid (GABA) from rat striatal slices without any effects of 30 mM K⁺ or 4-aminopyridine on basal and evoked efflux. The effects of amitriptyline on glutamate efflux were comparable to those on DA or GABA efflux. These effects of amitriptyline can be well explained by its blockade of voltage-dependent Na⁺ channels and may be independent of other activities of this drug such as re-uptake inhibition of monoamines and blockade of K⁺ channels.

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Compound action potential inhibition produced by various antidepressants in the frog sciatic nerve
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The CAP amplitude reductions produced by the antidepressants may be due to an inhibition of TTX-sensitive voltage-gated Na+ channels which are involved in the production of frog CAPs (Katsuki et al., 2006; Mizuta et al., 2008). In support of this idea, voltage-gated Na+ channels were inhibited by duloxetine (Stoetzer et al., 2016; Wang et al., 2010), fluoxetine (Pancrazio et al., 1998), amitriptyline (Ishii and Sumi, 1992; Leffler et al., 2007; Nicholson et al., 2002; Pancrazio et al., 1998; Song et al., 2000; Stoetzer et al., 2016; Wang et al., 2004; Yan et al., 2010), desipramine and maprotiline (Dick et al., 2007). The efficacy sequence of amitriptyline > fluoxetine ≧ desipramine for frog sciatic nerve CAP inhibition was similar to that of Na+-channel inhibition in bovine chromaffin cells (Pancrazio et al., 1998).
Although an inhibition of action potential conduction in nerve fibers possibly contributes to at least a part of antinociception produced by analgesics and the adjuvants, it has not been fully examined yet how the conduction inhibition differs in extent among their drugs. We investigated the effects of various antidepressants used as analgesic adjuvants on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. The results were compared with those of the other adjuvants that were reported previously. Antidepressants, duloxetine (serotonin and noradrenaline reuptake inhibitor, SNRI), fluoxetine (selective serotonin reuptake inhibitor, SSRI), amitriptyline (tricyclic tertiary amine), desipramine (tricyclic secondary amine) and maprotiline (tetracyclic secondary amine), reduced the peak amplitude of the CAP with half-maximal inhibitory concentration (IC₅₀) values of 0.23, 1.5, 0.26, 1.6 and 0.95 mM, respectively. Trazodone (non-SNRI, -SSRI, -tricyclic and -tetracyclic antidepressant) at 1.0 mM reduced CAP amplitude by about 50%. The duloxetine and amitriptyline values were comparable to those of lamotrigine and carbamazepine (antiepileptics), dexmedetomidine (α₂-adrenoceptor agonist) and ropivacaine, levobupivacaine and pramoxine (local anesthetics). The fluoxetine, desipramine, maprotiline and trazodone values were similar to those of oxymetazoline (α₂-adrenoceptor agonist) and lidocaine, cocaine, procaine and prilocaine (local anesthetics). The antidepressants’ IC₅₀ values were much larger than that of tetracaine (local anesthetic). In conclusion, the six antidepressants inhibited CAPs with efficacies comparable to some antiepileptics, α₂-adrenoceptor agonists and local anesthetics. It was suggested that antidepressants inhibit nerve conduction with efficacies comparable to those of the other adjuvants.
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Tricyclic antidepressants inhibit the presynaptic reuptake of the monoamines, serotonin and noradrenaline [25]. It has repeatedly been shown in experiments in vitro that tricyclic antidepressants block sodium channels and this effect is also seen in neuronal tissue [26–28]. Pregabalin is a more specific α2-δ ligand with a sixfold-higher binding affinity than gabapentin.
There is no head on comparison of amitriptyline (AMT) and pregabalin (PG) in relieving pain and disability in chronic low backache (CLBA). This randomized controlled trial reports the efficacy and safety of AMT and PG in CLBA.
Patients with CLBA, 15–65 years of age without specific cause and significant neurological deficit were included. Severity of pain was assessed by Visual Analogue Scale (VAS) and disability by Oswestry Disability Index (ODI). Patients were followed up at 6 and 14 weeks and their VAS score, ODI and side effect were noted. Primary outcome was pain relief (> 50% improvement in VAS score) at 14 weeks and secondary outcome were reduction in ODI (> 20%) and side effects.
200 patients with CLBA were randomized to AMT (n = 103) and PG (n = 97) using random numbers. The VAS score and ODI improved significantly following AMT and PG at 6 and 14 weeks compared to baseline. The improvement in pain (57.3% Vs 39.2%; P = 0.01) and disability (65% Vs 49.5%; P = 0.03) however was more in AMT group. The composite side effects were similar in both groups.
AMT and PG are effective in CLBA but AMT reduced pain and disability significantly compared to PG.
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Injury to peripheral or spinal nerves following either trauma or disease has several consequences including the development of neuropathic pain. This syndrome is often refractory against conventional analgesics; and thus, novel medicaments are desired for its treatment. Recent studies have emphasized that dysfunction of inhibitory neuronal regulation of pain signal transduction may be relevant to the development of neuropathic pain. Glycinergic neurons are localized in specific brain regions and the spinal cord, where they play an important role in the prevention of pathological pain symptoms. Thus, an enhancement of glycinergic control in the spinal cord is a promising strategy for pain relief from neuropathic pain.
Glycine transporter (GlyT) 1 and GlyT2, which are located in glial cells and neurons, respectively play important roles by clearing synaptically released glycine or supplying glycine to glycinergic neurons to regulate glycinergic neurotransmission. Thus, an inhibition of GlyTs could be used to modify pain signal transmission in the spinal cord. Recently developed specific inhibitors of GlyTs have made this possibility a reality. Both GlyT1 and GlyT2 inhibitors produced potential anti-nociceptive effect in various neuropathic pain models, chronic and acute inflammatory models in animals. Their anti-allodynia effects are mediated by the inhibition of GlyTs following activation of spinal glycine receptor α3. These results established GlyTs as target molecules for medicaments for neuropathic pain. Moreover, the phase-dependent anti-allodynia effects of GlyT inhibitors have provided important information on effective therapeutic strategies and also understanding the underlying molecular mechanisms of the development of neuropathic pain.
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Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used to investigate the long-term effect of hypothalamic–pituitary–adrenal axis dysfunction on brain dopamine transmission. Compared to control mice, the transgenic animals showed increased amphetamine-induced locomotor activity and increased concentrations of striatal dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Binding of [³H]SCH 23390 and [³H]spiperone to, respectively, D1 and D2 dopamine receptors was increased in transgenic mice. In contrast, autoradiography of striatal [³H]GBR 12935 binding to the dopamine transporter was decreased and the mRNA levels of this transporter, measured by in situ hybridization, remained unchanged in the substantia nigra pars compacta. The effect of chronic treatment for two weeks with amitriptyline or fluoxetine was compared in control and transgenic mice. No significant changes were observed in control mice following antidepressant treatment, whereas in transgenic mice both antidepressants reduced striatal [³H]SCH 23390 and [³H]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [³H]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compared to vehicle- or amitriptyline-treated transgenic mice.
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Local anesthetics and antiepileptic drugs having sodium channel–blocking abilities are effective in treating neuropathic pain. Finally, TCAs block potassium channels.69 Doxepin is a tertiary amine used in treatment of neurotic excoriations, chronic urticaria, and generalized pruritus.
Amitriptyline modulation of Na<sup>+</sup> channels in rat dorsal root ganglion neurons
2000, European Journal of Pharmacology
The effects of amitriptyline, a tricyclic antidepressant, on tetrodotoxin-sensitive and tetrodotoxin-resistant Na⁺ currents in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp method. Amitriptyline blocked both types of Na⁺currents in a dose-and holding potential-dependent manner. At the holding potential of −80 mV, the apparent dissociation constants (K_d) for amitriptyline to block tetrodotoxin-sensitive and tetrodotoxin-resistant Na⁺ channels were 4.7 and 105 μM, respectively. These values increased to 181 and 193 μM, respectively, when the membrane was held at a potential negative enough to remove the steady-state inactivation. Amitriptyline dose-dependently shifted the steady-state inactivation curves in the hyperpolarizing direction and increased the values of the slope factors for both types of Na⁺ channels. The voltage dependence of the activation of both types of Na⁺ channels was shifted in the depolarizing direction. It was concluded that amitriptyline blocked the two types of Na⁺ channels in rat sensory neurons by modulating the activation and the inactivation kinetics.

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¹: Research fellow from Omiya Research Laboratory, Nikken Chemical Co., Ltd., 1-346 Kitabukuro-Chyo, Omiya, Saitama 330, Japan.

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Short communicationAmitriptyline inhibits striatal efflux of neurotransmitters via blockade of voltage-dependent Na+ channels

Abstract

Biochcm. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Neurosci. Lett.

Eur. J. Pharmacol.

Short communication
Amitriptyline inhibits striatal efflux of neurotransmitters via blockade of voltage-dependent Na⁺ channels