MUSCARINIC FACILITATION OF GABA RELEASE IN SUBSTANTIA-GELATINOSA OF THE RAT SPINAL DORSAL HORN

1. Blind patch clamp recordings were made from substantia gelatinosa ( SG) neurones in the adult rat spinal cord slice to study the mechanism s of cholinergic modulation of GABAergic inhibition. 2. In the majorit y of SG neurones tested, carbachol (10 mu M) increased the frequency ( 677 % of control) of spontaneous GABAergic inhibitory postsynaptic cur rents (IPSCs). A portion of these events appeared to result from the g eneration of spikes by GABAergic interneurones, since large amplitude IPSCs were eliminated by tetrodotoxin (1 mu M). 3. The effect of carba chol on spontaneous IPSCs was mimicked by neostigmine, suggesting that GABAergic interneurones are under tonic regulation by cholinergic sys tems. 4. The frequency of GABAergic miniature IPSCs in the presence of tetrodotoxin (1 mu M) was also increased by carbachol without affecti ng amplitude distribution, indicating that acetylcholine facilitates q uantal release of GABA through presynaptic mechanisms 5. Neither the M -1 receptor agonist McN-A-343 (10-300 mu M) nor the M-2 receptor agoni st, arecaidine (10-100 mu M), mimicked the effects of carbachol. All e ffects of carbachol and neostigmine were antagonized by atropine (1 mu M), while pirenzepine (100 nM), methoctramine (1 mu M) and hexahydros iladifenidol hydrochloride, p-fluoro-analog (100 nM) had no effect. 6. Focal stimulation of deep dorsal horn, but not dorsolateral funiculus , evoked a similar increase in IPSC frequency to that evoked by carbac hol, and neostigmine. The stimulation induced facilitation of GABAergi c transmission lasted for 2-3 min post stimulation, and the effect was antagonized by atropine (100 nM). 7. Our observations suggest that GA BAergic interneurones possess muscarinic receptors on both axon termin als and somatodendritic sites, that the activation of these receptors increases the excitability of inhibitory interneurones and enhances GA BA release in SG and that the GABAergic inhibitory system is further c ontrolled by cholinergic neurones located in the deep dorsal horn. Tho se effects may be responsible for the antinociceptive action produced by the intrathecal administration of muscarinic agonists and acetylcho linesterase inhibitors.