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Up-regulation of spinal muscarinic receptors and increased antinociceptive effect of intrathecal muscarine in diabetic rats.
J Pharmacol Exp Ther. 2003 Nov; 307(2):676-81.JP

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]GTPgammaS) 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 mug muscarine in diabetic animals was potentiated significantly compared with that in normal animals. The maximal muscarine-stimulated [35S]GTPgammaS 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.

Authors+Show Affiliations

Department of Anesthesiology, Penn State University College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12966147

Citation

Chen, Shao-Rui, and Hui-Lin Pan. "Up-regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats." The Journal of Pharmacology and Experimental Therapeutics, vol. 307, no. 2, 2003, pp. 676-81.
Chen SR, Pan HL. Up-regulation of spinal muscarinic receptors and increased antinociceptive effect of intrathecal muscarine in diabetic rats. J Pharmacol Exp Ther. 2003;307(2):676-81.
Chen, S. R., & Pan, H. L. (2003). Up-regulation of spinal muscarinic receptors and increased antinociceptive effect of intrathecal muscarine in diabetic rats. The Journal of Pharmacology and Experimental Therapeutics, 307(2), 676-81.
Chen SR, Pan HL. Up-regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats. J Pharmacol Exp Ther. 2003;307(2):676-81. PubMed PMID: 12966147.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Up-regulation of spinal muscarinic receptors and increased antinociceptive effect of intrathecal muscarine in diabetic rats. AU - Chen,Shao-Rui, AU - Pan,Hui-Lin, Y1 - 2003/09/09/ PY - 2003/9/11/pubmed PY - 2003/12/12/medline PY - 2003/9/11/entrez SP - 676 EP - 81 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 307 IS - 2 N2 - 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]GTPgammaS) 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 mug muscarine in diabetic animals was potentiated significantly compared with that in normal animals. The maximal muscarine-stimulated [35S]GTPgammaS 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12966147/Up_regulation_of_spinal_muscarinic_receptors_and_increased_antinociceptive_effect_of_intrathecal_muscarine_in_diabetic_rats_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=12966147 DB - PRIME DP - Unbound Medicine ER -