Concerted action of antiepileptic and antidepressant agents to depress spinal neurotransmission: Possible use in the therapy of spasticity and chronic pain.
Chronic pain states and epilepsies are common therapeutic targets of voltage-gated sodium channel blockers. Inhibition of sodium channels results in central muscle relaxant activity as well. Selective serotonin reuptake inhibitors are also applied in the treatment of pain syndromes. Here, we investigate the pharmacodynamic interaction between these two types of drugs on spinal neurotransmission in vitro and in vivo. Furthermore, the ability of serotonin reuptake inhibitors to modulate the anticonvulsant and windup inhibitory actions and motor side effect of the sodium channel blocker lamotrigine was investigated. In the hemisected spinal cord model, we found that serotonin reuptake inhibitors increased the reflex inhibitory action of sodium channel blockers. The interaction was clearly more than additive. The potentiation was prevented by blocking 5-HT(2) receptors and PKC, and mimicked by activation of these targets by selective pharmacological tools, suggesting the involvement of 5-HT(2) receptors and PKC in the modulation of sodium channel function. The increase of sodium current blocking potency of lamotrigine by PKC activation was also demonstrated at cellular level, using the whole-cell patch clamp method. Similar synergism was found in vivo, in spinal reflex, windup, and maximal electroshock seizure models, but not in the rotarod test, which indicate enhanced muscle relaxant, anticonvulsant and analgesic activities with improved side effect profile. Our findings are in agreement with clinical observations suggesting that sodium channel blocking drugs, such as lamotrigine, can be advantageously combined with selective serotonin reuptake inhibitors in some therapeutic fields, and may help to understand the molecular mechanisms underlying the interaction.
Thán
Márta
M
Pharmacology and Drug Safety Research, Gedeon Richter Plc., P.O. Box 27, H-1475 Budapest 10, Hungary.
Kocsis
Pál
P
Tihanyi
Károly
K
Fodor
László
L
Farkas
Bence
B
Kovács
Gyula
G
Kis-Varga
Agnes
A
Szombathelyi
Zsolt
Z
Tarnawa
István
I
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D009128:Muscle Spasticity / Q000188:drug therapy / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010148:Intractable Pain / Q000188:drug therapy / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects; D012021:Reflex, Abnormal / Q000187:drug effects / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014227:Triazines / Q000494:pharmacology
D000927:Anticonvulsants; D000928:Antidepressive Agents; D000077213:Lamotrigine; D011493:Protein Kinase C; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014227:Triazines