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Naunyn Schmiedebergs Arch Pharmacol
2017 Dec 01;39012:1255-1270. doi: 10.1007/s00210-017-1424-x.
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Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes.
Horishita T, Yanagihara N, Ueno S, Okura D, Horishita R, Minami T, Ogata Y, Sudo Y, Uezono Y, Sata T, Kawasaki T.
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Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 with a β1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the β3 subunit on the effect of antidepressants on Nav1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with β1. The inhibitory effects were more potent for Nav1.3, Nav1.7, and Nav1.8, which are distributed in dorsal root ganglia, than Nav1.2 and Nav1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Nav1.7 with β1 was most potent with a half-maximal inhibitory concentration (IC50) 4.6 μmol/L. IC50 for amitriptyline on Nav1.3 coexpressed with β1 was lowered from 8.4 to 4.5 μmol/L by coexpression with β3. Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various α subunits. Moreover, the β3 subunit appears important for inhibition of Nav1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.
Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008, Pubmed
Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008,
Pubmed Akopian,
The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
1999,
Pubmed Arita,
Inhibition of 22Na influx by tricyclic and tetracyclic antidepressants and binding of [3H]imipramine in bovine adrenal medullary cells.
1987,
Pubmed Attal,
EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision.
2010,
Pubmed Barber,
Blockade of cardiac sodium channels by amitriptyline and diphenylhydantoin. Evidence for two use-dependent binding sites.
1991,
Pubmed Baron,
Neuropathic low back pain in clinical practice.
2016,
Pubmed Baron,
Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.
2010,
Pubmed Bräu,
Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons.
2001,
Pubmed Catterall,
From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.
2000,
Pubmed Catterall,
International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels.
2005,
Pubmed Chen,
Intrathecal tri-cyclic antidepressants produce spinal anesthesia.
2004,
Pubmed Cheng,
Pretreatment with intrathecal amitriptyline potentiates anti-hyperalgesic effects of post-injury intra-peritoneal amitriptyline following spinal nerve ligation.
2012,
Pubmed Cummins,
The roles of sodium channels in nociception: Implications for mechanisms of pain.
2007,
Pubmed Delpón,
Tonic and frequency-dependent Vmax block induced by (S)-nafenodone, a new antidepressant drug, in guinea-pig papillary muscles.
1991,
Pubmed Delpón,
Further characterization of the effects of imipramine on plateau membrane currents in guinea-pig ventricular myocytes.
1991,
Pubmed Dick,
Sodium channel blockade may contribute to the analgesic efficacy of antidepressants.
2007,
Pubmed Dworkin,
Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.
2010,
Pubmed Finnerup,
Algorithm for neuropathic pain treatment: an evidence based proposal.
2005,
Pubmed Fukuoka,
Comparative study of the distribution of the alpha-subunits of voltage-gated sodium channels in normal and axotomized rat dorsal root ganglion neurons.
2008,
Pubmed Gerner,
Topical amitriptyline in healthy volunteers.
2003,
Pubmed Goldstein,
Duloxetine vs. placebo in patients with painful diabetic neuropathy.
2005,
Pubmed Hains,
Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury.
2003,
Pubmed Horishita,
Neurosteroids allopregnanolone sulfate and pregnanolone sulfate have diverse effect on the α subunit of the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 expressed in xenopus oocytes.
2014,
Pubmed
,
Xenbase Ishii,
Amitriptyline inhibits striatal efflux of neurotransmitters via blockade of voltage-dependent Na+ channels.
1992,
Pubmed Joshi,
Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states.
2006,
Pubmed Karson,
Human brain fluoxetine concentrations.
1993,
Pubmed Khan,
Amitriptyline for prolonged cutaneous analgesia in the rat.
2002,
Pubmed Kopsky,
High doses of topical amitriptyline in neuropathic pain: two cases and literature review.
2012,
Pubmed Lambert,
Modulation of native and recombinant GABA(A) receptors by endogenous and synthetic neuroactive steroids.
2001,
Pubmed LANCE,
TREATMENT OF CHRONIC TENSION HEADACHE.
1964,
Pubmed Liang,
Blockade of Nav1.8 currents in nociceptive trigeminal neurons contributes to anti-trigeminovascular nociceptive effect of amitriptyline.
2014,
Pubmed Lindia,
Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats.
2005,
Pubmed Lynch,
Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial.
2005,
Pubmed Lynch,
Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study.
2005,
Pubmed Micó,
Antidepressants and pain.
2006,
Pubmed Nicholson,
Differential blockade of neuronal voltage-gated Na(+) and K(+) channels by antidepressant drugs.
2002,
Pubmed Ogata,
Block of sodium channels by psychotropic drugs in single guinea-pig cardiac myocytes.
1989,
Pubmed Saarto,
Antidepressants for neuropathic pain.
2005,
Pubmed Shah,
beta3, a novel auxiliary subunit for the voltage-gated sodium channel, is expressed preferentially in sensory neurons and is upregulated in the chronic constriction injury model of neuropathic pain.
2000,
Pubmed
,
Xenbase Song,
Amitriptyline modulation of Na(+) channels in rat dorsal root ganglion neurons.
2000,
Pubmed Sun,
The analgesia effect of duloxetine on post-operative pain via intrathecal or intraperitoneal administration.
2014,
Pubmed Takahashi,
Expression of auxiliary beta subunits of sodium channels in primary afferent neurons and the effect of nerve injury.
2003,
Pubmed Wang,
Block of neuronal Na+ channels by antidepressant duloxetine in a state-dependent manner.
2010,
Pubmed Wang,
Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain?
2011,
Pubmed Wang,
State-dependent block of voltage-gated Na+ channels by amitriptyline via the local anesthetic receptor and its implication for neuropathic pain.
2004,
Pubmed Watson,
Antidepressant drugs as adjuvant analgesics.
1994,
Pubmed Wood,
Voltage-gated sodium channels and pain pathways.
2004,
Pubmed Yang,
Lidocaine, carbamazepine, and imipramine have partially overlapping binding sites and additive inhibitory effect on neuronal Na+ channels.
2010,
Pubmed Yeomans,
Decrease in inflammatory hyperalgesia by herpes vector-mediated knockdown of Nav1.7 sodium channels in primary afferents.
2005,
Pubmed
