Elsevier

Neuroscience

Volume 125, Issue 1, 2004, Pages 141-148
Neuroscience

Activation of muscarinic receptors inhibits spinal dorsal horn projection neurons: role of GABAB receptors

https://doi.org/10.1016/j.neuroscience.2004.01.015Get rights and content

Abstract

Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors produce efficacious analgesia. However, the mechanisms of the antinociceptive actions of muscarinic agonists in the spinal cord are not fully known. Previous in vitro studies have shown that muscarinic agonists increase GABA release and reduce the glutamatergic synaptic input to lamina II interneurons through GABAB receptors in the spinal cord. In the present study, we studied the effect of muscarinic agents on dorsal horn projection neurons and the role of spinal GABAB receptors in their action. Single-unit activity of ascending dorsal horn neurons was recorded in the lumbar spinal cord of anesthetized rats. The responses of dorsal horn neurons to graded mechanical stimuli were determined before and after topical spinal application of muscarine and neostigmine. We found that topical application of 0.1–5 μM muscarine or 0.5–5 μM neostigmine significantly suppressed the evoked response of dorsal horn neurons in a concentration-dependent manner. The inhibitory effect of muscarine or neostigmine on dorsal horn neurons was completely abolished in the presence of 1 μM atropine and by intrathecal pretreatment with 1 μg pertussis toxin to inactivate inhibitory G proteins. Furthermore, the inhibitory effect of both muscarine and neostigmine on the evoked response of dorsal horn neurons was significantly attenuated in the presence of 1 μM CGP55845, a GABAB receptor antagonist. Collectively, these data suggest that muscarinic agents inhibit dorsal horn projection neurons through muscarinic receptors coupled to pertussis toxin-sensitive Gi/o proteins. The inhibitory action of muscarinic agonists on these dorsal horn neurons is mediated in part by spinal GABAB receptors.

Section snippets

General procedures

Male rats (Harlan Sprague–Dawley, Indianapolis, IN, USA) weighing 380–400 g were used in all experiments. The experimental procedures and protocols were approved by the Animal Care and Use Committee of the Pennsylvania State University College of Medicine and conformed to the NIH guidelines on the ethical use of animals. Anesthesia was initially induced with 2% halothane in 100% oxygen. The left jugular vein and carotid artery were cannulated for i.v. drug administration and blood pressure

Results

A total of 57 ascending dorsal horn neurons from 51 rats was studied. All the dorsal horn projection neurons included in this study were wide-dynamic-range neurons. The ascending dorsal horn neurons recorded in the lumbar spinal cord had a mean depth of 563±21 μm, ranging from 324 to 827 μm.

Discussion

This is the first study demonstrating the inhibitory effect of muscarine and neostigmine on functionally identified ascending dorsal horn projection neurons and the role of spinal GABAB receptors in this action. In the present study, we found that both muscarine and neostigmine significantly inhibited the evoked response of ascending dorsal horn neurons. Furthermore, muscarine failed to inhibit the evoked response of dorsal horn neurons in rats pre-treated with intrathecal pertussis toxin.

Acknowledgements

This study was supported by the National Institutes of Health grants GM64830 and NS45602. H. L. Pan was a recipient of an Independent Scientist Award supported by the National Institutes of Health during the course of this study.

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