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Intrathecal clonidine suppresses phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain.
Anesth Analg. 2008 Aug; 107(2):693-700.A&A

Abstract

BACKGROUND

Intrathecal (IT) administration of the alpha-2 adrenoceptor agonist, clonidine, produces significant analgesic effects. Although several mechanisms underlying clonidine-induced analgesia have been proposed, the possible interaction with N-methyl-D-aspartate (NMDA) receptors as a major antinociceptive mechanism has not been addressed. We designed the present study to determine whether clonidine or other analgesics can affect spinal NMDA receptor activation in rats with chronic constriction injury (CCI)-induced neuropathy.

METHODS

Rats underwent unilateral CCI, and received IT clonidine (1, 5, 20 microg/rat), [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO, mu opioid receptor agonist, 1 microg/rat), gabapentin (anticonvulsant, 100 microg/rat) or vehicle 2 wks later. After drug injection, we measured the pain response to thermal or mechanical stimuli and used immunohistochemistry to evaluate spinal cord phosphorylated NMDA-receptor subunit 1 (pNR1) expression.

RESULTS

Two weeks after CCI surgery, rats displayed significant mechanical allodynia and thermal hyperalgesia, and the spinal cord dorsal horn showed a significant increase in the number of pNR1 immunoreactive neurons. IT injection of clonidine (20 microg/rat), DAMGO and gabapentin potently reduced mechanical allodynia and thermal hyperalgesia. Importantly, IT clonidine, but not IT DAMGO or gabapentin, dose-dependently reduced CCI-induced pNR1 expression in all lamina of the spinal cord dorsal horn by 30 min after injection. In addition, IT injection of the alpha-2 adrenoceptor antagonist, idazoxan (40 microg/rat) 10 min before clonidine injection completely reversed clonidine's antihyperalgesic and antiallodynic effects, as well as clonidine's suppressive effect on CCI-induced NR1 phosphorylation in the spinal cord dorsal horn.

CONCLUSIONS

Our data indicate that IT clonidine's antihyperalgesic/antiallodynic effect on neuropathic pain is associated with a significant reduction in spinal NMDA receptor phosphorylation and suggests a potentially novel mechanism of clonidine's action.

Authors+Show Affiliations

Department of Veterinary Physiology, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University, Seoul, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

18633054

Citation

Roh, Dae-Hyun, et al. "Intrathecal Clonidine Suppresses Phosphorylation of the N-methyl-D-aspartate Receptor NR1 Subunit in Spinal Dorsal Horn Neurons of Rats With Neuropathic Pain." Anesthesia and Analgesia, vol. 107, no. 2, 2008, pp. 693-700.
Roh DH, Kim HW, Yoon SY, et al. Intrathecal clonidine suppresses phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain. Anesth Analg. 2008;107(2):693-700.
Roh, D. H., Kim, H. W., Yoon, S. Y., Seo, H. S., Kwon, Y. B., Han, H. J., Beitz, A. J., & Lee, J. H. (2008). Intrathecal clonidine suppresses phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain. Anesthesia and Analgesia, 107(2), 693-700. https://doi.org/10.1213/ane.0b013e31817e7319
Roh DH, et al. Intrathecal Clonidine Suppresses Phosphorylation of the N-methyl-D-aspartate Receptor NR1 Subunit in Spinal Dorsal Horn Neurons of Rats With Neuropathic Pain. Anesth Analg. 2008;107(2):693-700. PubMed PMID: 18633054.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intrathecal clonidine suppresses phosphorylation of the N-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain. AU - Roh,Dae-Hyun, AU - Kim,Hyun-Woo, AU - Yoon,Seo-Yeon, AU - Seo,Hyoung-Sig, AU - Kwon,Young-Bae, AU - Han,Ho-Jae, AU - Beitz,Alvin J, AU - Lee,Jang-Hern, PY - 2008/7/18/pubmed PY - 2008/8/30/medline PY - 2008/7/18/entrez SP - 693 EP - 700 JF - Anesthesia and analgesia JO - Anesth Analg VL - 107 IS - 2 N2 - BACKGROUND: Intrathecal (IT) administration of the alpha-2 adrenoceptor agonist, clonidine, produces significant analgesic effects. Although several mechanisms underlying clonidine-induced analgesia have been proposed, the possible interaction with N-methyl-D-aspartate (NMDA) receptors as a major antinociceptive mechanism has not been addressed. We designed the present study to determine whether clonidine or other analgesics can affect spinal NMDA receptor activation in rats with chronic constriction injury (CCI)-induced neuropathy. METHODS: Rats underwent unilateral CCI, and received IT clonidine (1, 5, 20 microg/rat), [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO, mu opioid receptor agonist, 1 microg/rat), gabapentin (anticonvulsant, 100 microg/rat) or vehicle 2 wks later. After drug injection, we measured the pain response to thermal or mechanical stimuli and used immunohistochemistry to evaluate spinal cord phosphorylated NMDA-receptor subunit 1 (pNR1) expression. RESULTS: Two weeks after CCI surgery, rats displayed significant mechanical allodynia and thermal hyperalgesia, and the spinal cord dorsal horn showed a significant increase in the number of pNR1 immunoreactive neurons. IT injection of clonidine (20 microg/rat), DAMGO and gabapentin potently reduced mechanical allodynia and thermal hyperalgesia. Importantly, IT clonidine, but not IT DAMGO or gabapentin, dose-dependently reduced CCI-induced pNR1 expression in all lamina of the spinal cord dorsal horn by 30 min after injection. In addition, IT injection of the alpha-2 adrenoceptor antagonist, idazoxan (40 microg/rat) 10 min before clonidine injection completely reversed clonidine's antihyperalgesic and antiallodynic effects, as well as clonidine's suppressive effect on CCI-induced NR1 phosphorylation in the spinal cord dorsal horn. CONCLUSIONS: Our data indicate that IT clonidine's antihyperalgesic/antiallodynic effect on neuropathic pain is associated with a significant reduction in spinal NMDA receptor phosphorylation and suggests a potentially novel mechanism of clonidine's action. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/18633054/Intrathecal_clonidine_suppresses_phosphorylation_of_the_N_methyl_D_aspartate_receptor_NR1_subunit_in_spinal_dorsal_horn_neurons_of_rats_with_neuropathic_pain_ L2 - https://doi.org/10.1213/ane.0b013e31817e7319 DB - PRIME DP - Unbound Medicine ER -