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Research ArticleNEUROPHARMACOLOGY

Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Shao-Rui Chen and Hui-Lin Pan
Journal of Pharmacology and Experimental Therapeutics November 2003, 307 (2) 676-681; DOI: https://doi.org/10.1124/jpet.103.055905
Shao-Rui Chen
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Hui-Lin Pan
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Abstract

Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors produce effective pain relief. Intrathecal injection of a small dose of neostigmine produces a profound antiallodynic effect in rats with diabetic neuropathy. However, the mechanisms of increased antinociceptive effect of cholinergic agents on diabetic neuropathic pain are not clear. In the present study, we tested the hypothesis that spinal muscarinic receptors are up-regulated in diabetes. The withdrawal threshold of the hindpaw in response to noxious heat and pressure stimuli was determined in streptozotocin-induced diabetic and age-matched normal rats. Muscarine-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding was used to assess the change of functional muscarinic receptors in the spinal cord in diabetes. The [3H]AF-DX 384 membrane binding was performed to determine the number and affinity of spinal cord M2 muscarinic receptors in normal and diabetic rats. We found that the antinociceptive effect of intrathecal 2 to 12 μg muscarine in diabetic animals was potentiated significantly compared with that in normal animals. The maximal muscarine-stimulated [35S]GTPγS binding was 112.5 ± 8.3% in normal rats and 168.8 ± 12.1% (P < 0.05) in diabetic rats. Although the KD value (2.9 nM) was similar in both groups, the Bmax of [3H]AF-DX 384 membrane binding was significantly higher in diabetic than in normal rats (255.2 ± 5.9 versus 165.9 ± 3.5 fmol/mg protein, P < 0.05). Collectively, these data strongly suggest that the muscarinic receptor is up-regulated in the dorsal spinal cord in diabetic rats. This finding probably accounts for the increased efficacy of the antinociceptive effect of intrathecal muscarinic agonists in diabetic neuropathic pain.

Footnotes

  • This study was supported by Grants NS45602 and NS41178 cofunded by the National Institutes of Health and the Juvenile Diabetes Foundation International. H. L. Pan was a recipient of an Independent Scientist Award supported by the National Institutes of Health during the course of this study.

  • DOI: 10.1124/jpet.103.055905.

  • ABBREVIATION: [35S]GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate.

    • Received June 18, 2003.
    • Accepted July 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 2
1 Nov 2003
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Research ArticleNEUROPHARMACOLOGY

Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Shao-Rui Chen and Hui-Lin Pan
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 676-681; DOI: https://doi.org/10.1124/jpet.103.055905

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Research ArticleNEUROPHARMACOLOGY

Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Shao-Rui Chen and Hui-Lin Pan
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 676-681; DOI: https://doi.org/10.1124/jpet.103.055905
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