Activations of muscarinic M1receptors in the anterior cingulate cortex contribute to the antinociceptive effect via GABAergic transmission.
Background Cholinergic systems regulate the synaptic transmission resulting in the contribution of the nociceptive behaviors. Anterior cingulate cortex is a key cortical area to play roles in nociception and chronic pain. However, the effect of the activation of cholinergic system for nociception is still unknown in the cortical area. Here, we tested whether the activation of cholinergic receptors can regulate nociceptive behaviors in adult rat anterior cingulate cortex by integrative methods including behavior, immunohistochemical, and electrophysiological methods. Results We found that muscarinic M1receptors were clearly expressed in the anterior cingulate cortex. Using behavioral tests, we identified that microinjection of a selective muscarinic M1receptors agonist McN-A-343 into the anterior cingulate cortex dose dependently increased the mechanical threshold. In contrast, the local injection of McN-A-343 into the anterior cingulate cortex showed normal motor function. The microinjection of a selective M1receptors antagonist pirenzepine blocked the McN-A-343-induced antinociceptive effect. Pirenzepine alone into the anterior cingulate cortex decreased the mechanical thresholds. The local injection of the GABAAreceptors antagonist bicuculline into the anterior cingulate cortex also inhibited the McN-A-343-induced antinociceptive effect and decreased the mechanical threshold. Finally, we further tested whether the activation of M1receptors could regulate GABAergic transmission using whole-cell patch-clamp recordings. The activation of M1receptors enhanced the frequency of spontaneous and miniature inhibitory postsynaptic currents as well as the amplitude of spontaneous inhibitory postsynaptic currents in the anterior cingulate cortex. Conclusions These results suggest that the activation of muscarinic M1receptors in part increased the mechanical threshold by increasing GABAergic transmitter release and facilitating GABAergic transmission in the anterior cingulate cortex.
1 Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Japan.
Kohei
K
Koga
2 Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Yu
Y
Matsuzaki
2 Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Kenji
K
Honda
2 Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Fumihiro
F
Eto
1 Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Japan.
Tomonori
T
Furukawa
3 Department of Drug Informatics, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Keisuke
K
Migita
2 Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Keiichi
K
Irie
2 Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Kenichi
K
Mishima
1 Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Japan.
Shinya
S
Ueno
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology / Q000627:therapeutic use; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
D000700:Analgesics; D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D005680:gamma-Aminobutyric Acid
GABA receptors; McN-A-343; Muscarinic M1 receptor; anterior cingulate cortex; antinociception; mechanical stimulation