Concerted action of antiepileptic and antidepressant agents to depress spinal neurotransmission: Possible use in the therapy of spasticity and chronic pain

• Published in: Neurochemistry international 2007-03, Vol.50 (4), p.642-652
• Main Authors: Thán, Márta, Kocsis, Pál, Tihanyi, Károly, Fodor, László, Farkas, Bence, Kovács, Gyula, Kis-Varga, Ágnes, Szombathelyi, Zsolt, Tarnawa, István
• Format: Article
• Language: English
• Subjects: Afferent Pathways - drug effects; Afferent Pathways - metabolism; Afferent Pathways - physiopathology; Animals; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Antidepressive Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Chronic pain; Drug Synergism; Fundamental and applied biological sciences. Psychology; Male; Medical sciences; Mice; Muscle Spasticity - drug therapy; Muscle Spasticity - physiopathology; Neural Inhibition - drug effects; Neural Inhibition - physiology; Neuropharmacology; Nociceptors - drug effects; Nociceptors - physiology; Organ Culture Techniques; Pain, Intractable - drug therapy; Pain, Intractable - physiopathology; Pharmacodynamic interaction; Pharmacology. Drug treatments; Posterior Horn Cells - drug effects; Posterior Horn Cells - metabolism; Posterior Horn Cells - physiopathology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT2C - drug effects; Reflex, Abnormal - drug effects; Reflex, Abnormal - physiology; Serotonin 5-HT2 Receptor Antagonists; Serotonin reuptake inhibitors; Serotonin Uptake Inhibitors - pharmacology; Sodium Channel Blockers - pharmacology; Sodium channels; Sodium Channels - drug effects; Sodium Channels - metabolism; Spasticity; Spinal reflexes; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Triazines - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2006.12.008

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.