Abstract

Activation of muscarinic acetylcholine receptors (mAChRs) in the spinal cord inhibits pain transmission. At least three mAChR subtypes (M(2), M(3), and M(4)) are present in the spinal dorsal horn. However, it is not clear how each mAChR subtype contributes to the regulation of glutamatergic input to dorsal horn neurons. We recorded spontaneous excitatory postsynaptic currents (sEPSCs) from lamina II neurons in spinal cord slices from wild-type (WT) and mAChR subtype knock-out (KO) mice. The mAChR agonist oxotremorine-M increased the frequency of glutamatergic sEPSCs in 68.2% neurons from WT mice and decreased the sEPSC frequency in 21.2% neurons. Oxotremorine-M also increased the sEPSC frequency in ∼50% neurons from M(3)-single KO and M(1)/M(3) double-KO mice. In addition, the M(3) antagonist J104129 did not block the stimulatory effect of oxotremorine-M in the majority of neurons from WT mice. Strikingly, in M(5)-single KO mice, oxotremorine-M increased sEPSCs in only 26.3% neurons, and J104129 abolished this effect. In M(2)/M(4) double-KO mice, but not M(2)- or M(4)-single KO mice, oxotremorine-M inhibited sEPSCs in significantly fewer neurons compared with WT mice, and blocking group II/III metabotropic glutamate receptors abolished this effect. The M(2)/M(4) antagonist himbacine either attenuated the inhibitory effect of oxotremorine-M or potentiated the stimulatory effect of oxotremorine-M in WT mice. Our study demonstrates that activation of the M(2) and M(4) receptor subtypes inhibits synaptic glutamate release to dorsal horn neurons. M(5) is the predominant receptor subtype that potentiates glutamatergic synaptic transmission in the spinal cord.

Highlights

  • Activation of muscarinic acetylcholine receptors in the spinal cord inhibits pain transmission

  • Effects of Oxotremorine-M on spontaneous excitatory postsynaptic currents (sEPSCs) and miniature EPSCs (mEPSCs) of Lamina II Neurons in WT Mice—To determine the role of muscarinic acetylcholine receptors (mAChRs) in the control of synaptic glutamate release to lamina II neurons, we first examined the effect of oxotremorine-M, a specific agonist that stimulates all mAChR subtypes, on glutamatergic sEPSCs in WT mice

  • Effects of Oxotremorine-M on sEPSCs and mEPSCs of Lamina II Neurons in M5-KO Mice—Because the stimulatory effect of oxotremorine-M on sEPSCs was still present in the majority of neurons in the M1/M3 double-KO mice, we used M5-KO mice to determine whether the M5 subtype contributed to the mAChR activation-induced synaptic glutamate release in the spinal cord

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Summary

Introduction

Activation of muscarinic acetylcholine receptors (mAChRs) in the spinal cord inhibits pain transmission. These data suggest that the M2/M4 subtypes mediate the inhibitory effect of the mAChR agonist on synaptic glutamate release to spinal dorsal horn neurons.

Results
Conclusion
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