Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn.
While the mechanisms underlying nicotinic acetylcholine receptor (nAChR)-mediated analgesia remain unresolved, one process that is almost certainly involved is the recently-described nicotinic enhancement of inhibitory synaptic transmission in the spinal cord dorsal horn. Despite these observations, the prototypical nicotinic analgesic (epibatidine) has not yet been shown to modulate inhibitory transmission in the spinal cord. Furthermore, while nAChRs have been implicated in short-term modulation, no studies have investigated the role of nAChRs in the modulation of long-term synaptic plasticity of inhibitory transmission in dorsal horn. Whole-cell patch clamp recordings from dorsal horn neurons of neonatal rat spinal cord slices were therefore conducted to investigate the short- and long-term effects of nicotinic agonists on GABAergic transmission. GABAergic synaptic transmission was enhanced in 86% of neurons during applications of 1 microM nicotine (mean increased spontaneous GABAergic inhibitory postsynaptic current (sIPSC) frequency was approximately 500% of baseline). Epibatidine (100 nM) induced an increase to an average of approximately 3000% of baseline, and this effect was concentration dependent (EC50=43 nM). Nicotinic enhancement was inhibited by mecamylamine and DHbetaE, suggesting an important role for non-alpha7 nAChRs. Tetrodotoxin (TTX) did not alter the prevalence or magnitude of the effect of nicotine, but the responses had a shorter duration. Nicotine did not alter evoked GABAergic IPSC amplitude, yet the long-term depression (LTD) induced by strong stimulation of inhibitory inputs was reduced when paired with nicotine. These results provide support for a mechanism of nicotinic analgesia dependent on both short and long-term modulation of GABAergic synaptic transmission in the spinal cord dorsal horn.
Genzen
Jonathan R
JR
Committee on Neurobiology, University of Chicago, Chicago, IL 60637, USA.
McGehee
Daniel S
DS
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008159:Lumbar Vertebrae; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism*; D018009:Receptors, Glycine / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D018079:Receptors, GABA; D018009:Receptors, Glycine; D011978:Receptors, Nicotinic; D009538:Nicotine; C082748:epibatidine