Effects of lacosamide, a novel sodium channel modulator, on dorsal horn neuronal responses in a rat model of neuropathy

• Published in: Neuropharmacology 2009-09, Vol.57 (4), p.472-479
• Main Authors: Bee, Lucy Ann, Dickenson, Anthony H.
• Format: Article
• Language: English
• Subjects: Acetamides - administration & dosage; Acetamides - pharmacology; Action Potentials; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Evoked Potentials; Lacosamide; Lumbar Vertebrae; Male; Microelectrodes; Neuropathy; Pain; Pain - drug therapy; Pain - physiopathology; Pain Measurement; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - physiopathology; Posterior Horn Cells - drug effects; Posterior Horn Cells - physiopathology; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers - administration & dosage; Sodium Channel Blockers - pharmacology; Sodium channels; Spinal cord; Spinal Nerves - injuries; Time Factors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2009.06.021

Various mechanisms underlie the complexity of neuropathic pain (pain due to disease of the somatosensory system), with each mechanism bearing a different order of relevance from one person and pain state to the next. Successful treatment is contingent on sound knowledge of underlying mechanisms that may occur at peripheral, spinal and/or supraspinal sites. In particular, ion channels throughout the nervous system are known to play an intimate part in neuropathic pain, and thus stand as good targets for analgesic drugs. Agents that modulate voltage-gated sodium channel function can reduce action potential propagation along sensory neurones to reduce the transmission and perception of nociceptive signals. Lacosamide is a functionalised amino acid that affects voltage-gated sodium channels in a novel way by enhancing the slow inactivating ‘braking’ state of these channels. To validate lacosamide's inhibitory efficacy in vivo, we unilaterally ligated spinal nerves L5 and L6 in rats to induce a state of neuropathy, and on post-operative days 14–17 recorded evoked-responses of deep dorsal horn neurones before and after spinal or systemic lacosamide delivery. Lacosamide's effects on various measures in spinal nerve-ligated rats were compared to rats that underwent sham surgery. Our results show that neuropathy induced novel inhibitory effects of lacosamide on mechanical and electrical responses, and enhanced inhibitory effects on thermal responses after systemic or spinal administration, suggesting state-preference actions of lacosamide.