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Involvement of spinal GABA receptors in the regulation of intraspinal acetylcholine relase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2005 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 525, no 1-3, 69-73 p.Article in journal (Refereed) Published
Abstract [en]

It has been shown that analgesics such as morphine, lidocaine and clonidine increase the release of spinal acetylcholine. Acetylcholine may therefore play an important role in the regulation of spinal pain threshold. Since behavioral as well as in vitro studies have shown a clear involvement of GABA (gamma-amino butyric acid) receptors in the regulation of spinal nociceptive mechanisms, the present study focused on the role of GABA receptors for spinal acetylcholine release control. GABA receptor agonists and antagonists were infused via a spinal microdialysis probe and acetylcholine release was measured. The GABA(A) receptor agonist muscimol decreased acetylcholine release and the antagonist bicuculline increased acetylcholine release. The GABA(B) receptor agonist baclofen decreased acetylcholine release whereas the antagonist saclofen did not change acetylcholine release. The results suggest that both GABA receptor subtypes have an inhibitory role on spinal dorsal horn acetylcholine release and that the GABA(A) receptors are tonically regulating acetylcholine release.

Place, publisher, year, edition, pages
2005. Vol. 525, no 1-3, 69-73 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93472DOI: 10.1016/j.ejphar.2005.08.035PubMedID: 16297380OAI: oai:DiVA.org:uu-93472DiVA: diva2:166956
Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2013-03-22Bibliographically approved
In thesis
1. Spinal Acetylcholine Release: Mechanisms and Receptor Involvement
Open this publication in new window or tab >>Spinal Acetylcholine Release: Mechanisms and Receptor Involvement
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Impulses coming from peripheries are modified in the spinal cord and transmitted to the brain. Several neurotransmitters have been involved in the processing of impulses in the spinal dorsal horn. Acetylcholine (ACh) is one of many neurotransmitters involved in the regulation of nociception in the spinal cord. In this study we investigated the role of nicotinic, muscarinic, serotonergic and GABA receptors in the regulation of spinal ACh release since these receptors are reported to be involved in spinal nociceptive processes.

Different receptor ligands were infused intraspinally via microdialysis and the spinal ACh release was measured by on-line HPLC. Receptor-ligand binding studies were performed with spinal cord homogenates as well as receptors expressed in cells.

In the first study, we found that nicotine and some of the nicotinic antagonists used increased ACh release suggesting that spinal ACh release is regulated by different nAChRs. Nicotine and nicotinic agonists may act on different types of receptors with different affinity to produce the observed net effect of increased ACh release. We propose the possibility of an involvement of three different nicotinic receptor subtypes in the regulation of spinal ACh release.

The effect of epibatidine, which is regarded as a nicotinic agonist, on muscarinic receptors was investigated in the second study. We propose that epibatidine, in μM concentrations, is a partial muscarinic receptor agonist that may interact with spinal muscarinic receptors to increase ACh release. The dual action on both nAChRs and mAChRs may explain the potent analgesic effect observed after intra-spinal epibatidine administration.

In the third study, we investigated the role of serotonin receptor involvement in ACh release control. The results suggest that only 5-HT1A and 5-HT2A receptors are involved in spinal ACh release. Considering current knowledge, the most probable location of 5-HT2A receptors is on cholinergic neurones. On activation of the 5-HT2A receptors the cellular excitability of cholinergic neurones is increased which results in an increasing ACh release. The 5-HT1A receptors might be located on cell bodies of GABA neurones which inhibit the firing rate of the GABA neurones when activated by serotonin.

In the fourth study, we investigated the GABA receptor involvement in the regulation in spinal ACh release. We found that GABAA receptors are tonically inhibiting spinal ACh release. The results further suggest that GABAB receptors also are involved in the regulation of spinal ACh release. However, unlike GABAA antagonists, GABAB antagonists do not increase ACh release. This suggests that GABAB receptors are not tonically regulating the spinal ACh release.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 39 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 70
Keyword
Neurosciences, acetylcholine release, spinal antinociception, nicotinic receptor, serotonin, GABA, Neurovetenskap
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-5931 (URN)91-554-6337-1 (ISBN)
Public defence
2005-10-14, B42, BMC, Husargatan 3, 75123, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-09-21 Created: 2005-09-21Bibliographically approved

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