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Acetylcholine in Spinal Pain Modulation: An in vivo Study in the Rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The spinal cord is an important component in the processing and modulation of painful stimuli. Nerve signals from the periphery are relayed and further conducted to the brain (nociception) in the spinal cord, and the most essential modulation of painful information (antinociception) occurs here. Several neurotransmitters are involved in spinal pain modulation, among them acetylcholine. However, the role of acetylcholine has previously been little investigated.

In the present thesis, the acetylcholine release in the spinal cord was studied in vivo. By using spinal microdialysis on anaesthetised rats, the effects on the intraspinal acetylcholine release of various receptor ligands and analgesic agents were examined. This, together with pain behavioural tests and in vitro pharmacological assays, was used to evaluate the role of acetylcholine in spinal pain modulation. The four studies in this thesis resulted in the following conclusions:

An increased release of spinal acetylcholine is associated with an elevated pain threshold, while a decreased acetylcholine release is associated with hyperalgesia, as seen after systemic treatment with a muscarinic agonist and an antagonist.

Lidocaine is a potent analgesic when given systemically. It was found to produce an increase of intraspinal acetylcholine after intravenous injection of analgesic doses. This effect was attenuated after muscarinic, and abolished after nicotinic, receptor blockade.

Various a2-adrenergic ligands, associated with nociceptive or antinociceptive effects, were found to affect intraspinal acetylcholine release via action on nicotinic receptors.

Finally, the involvement of spinal acetylcholine in the analgesic effects of aspirin and paracetamol was examined. It was found that spinal acetylcholine could participate in the analgesic effects of aspirin, but not of paracetamol.

The present thesis provides data that clearly demonstrate a relationship between intraspinal acetylcholine and antinociception, and elucidate interactions between acetylcholine and other mechanisms that mediate antinociception in the spinal cord.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 19
Keywords [en]
Laboratory animals, Pain, Nociception, Antinociception, Acetylcholine, Muscarinic, Nicotinic, Spinal cord, Microdialysis
Keywords [sv]
Försöksdjursvetenskap
National Category
Biomedical Laboratory Science/Technology
Identifiers
URN: urn:nbn:se:uu:diva-4834ISBN: 91-554-6178-6 (print)OAI: oai:DiVA.org:uu-4834DiVA, id: diva2:165926
Public defence
2005-04-22, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2005-03-30 Created: 2005-03-30 Last updated: 2009-10-14Bibliographically approved
List of papers
1. Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats
Open this publication in new window or tab >>Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats
2002 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 90, no 4, p. 187-192Article in journal (Refereed) Published
Abstract [en]

Abstract:Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10–300 μg/kg) and atropine (0.1, 10, 5000 μg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2–C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 μg/kg), or subcutaneously with oxotremorine (30, 100, 300 μg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 μg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 μg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.

Place, publisher, year, edition, pages
Blackwell, 2002
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-7215 (URN)10.1034/j.1600-0773.2002.900403.x (DOI)
Available from: 2006-10-18 Created: 2006-10-18 Last updated: 2017-12-14Bibliographically approved
2. Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats
Open this publication in new window or tab >>Intravenously administered lidocaine in therapeutic doses increases the intraspinal release of acetylcholine in rats
2002 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 317, no 2, p. 93-6Article in journal (Refereed) Published
Abstract [en]

The local anesthetic lidocaine suppresses different pain conditions when administered systemically. Part of the antinociceptive effect appears to be mediated via receptor mechanisms. We have previously shown that muscarinic and nicotinic agonists that produce antinociception increase the intraspinal release of acetylcholine. In the present study it was hypothesized that systemically administered lidocaine is acting through the same mechanisms as cholinergic agonists and affects the intraspinal release of acetylcholine. Microdialysis probes were placed in anesthetized rats for sampling of acetylcholine. Ten and 30 mg/kg lidocaine injected intravenously significantly increased the intraspinal release of acetylcholine. The effect of lidocaine could be reduced by pretreatment with intraspinally administered atropine or mecamylamine. Our results suggest that the antinociceptive effect produced by systemically administered lidocaine is mediated through an action on muscarinic and nicotinic receptors.

Place, publisher, year, edition, pages
Elsevier, 2002
Keywords
Lidocaine; Spinal cord; Pain; Microdialysis; Acetylcholine; Muscarinic; Nicotinic
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-7227 (URN)10.1016/S0304-3940(01)02440-5 (DOI)
Available from: 2006-10-24 Created: 2006-10-24 Last updated: 2017-12-14Bibliographically approved
3. The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat
Open this publication in new window or tab >>The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat
2004 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 94, no 4, p. 153-60Article in journal (Refereed) Published
Abstract [en]

Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinalacetylcholine. The cholinergic receptor system interacts with several other receptor types, such as a2-adrenergic receptors.To fully understand these interactions, the effects of various receptor ligands on the cholinergic system must be investigatedin detail. This study was initiated to investigate the effects of the a2-adrenergic receptor agonists clonidine and rilmenidineand the a2-adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors in the rat. Spinalmicrodialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or withoutnicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptorswere investigated. It was found that clonidine and rilmenidine increased, while yohimbine decreased spinal acetylcholinerelease. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade atten-uated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand, allligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curveand rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested a2-adrenergicreceptor ligands affect intraspinal acetylcholine release in the rat evoked by nicotinic receptor mechanisms in vivo, andthat they possess binding affinity to nicotinic receptors in vitro. The binding of a2-adrenergic receptor ligands to nicotinicreceptors might affect the intraspinal release of acetylcholine.

Place, publisher, year, edition, pages
Blackwell, 2004
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-92739 (URN)10.1111/j.1742-7843.2004.pto940401.x (DOI)15078339 (PubMedID)
Available from: 2005-03-30 Created: 2005-03-30 Last updated: 2017-12-14Bibliographically approved
4. Spinal cholinergic involvement after treatment with aspirin and paracetamol in rats
Open this publication in new window or tab >>Spinal cholinergic involvement after treatment with aspirin and paracetamol in rats
2004 In: Neurosci. Lett., ISSN 0304-3940, Vol. 368, no 1, p. 116-120Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92740 (URN)
Available from: 2005-03-30 Created: 2005-03-30Bibliographically approved

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