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Monoamine-dependent, opioid-independent antihypersensitivity effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a postoperative pain model in rats.
J Pharmacol Exp Ther. 2010 Sep 01; 334(3):1059-65.JP

Abstract

The neurotransmitters serotonin (5-HT) and noradrenaline (NA) have important roles in suppressing nociceptive transmission in the spinal cord. In the present study, we determined the efficacy and nature of the antihypersensitivity effects of milnacipran, a 5-HT and NA reuptake inhibitor (SNRI), in the spinal cord in a rat model of postoperative pain. Sprague-Dawley rats were used in all experiments. An incision was made on the plantar aspect of the hind paw. Mechanical hypersensitivity was measured by determining the withdrawal threshold to von Frey filaments applied to the paw. Drugs were administered intrathecally 24 h after paw incision. Microdialysis studies of the dorsal horn of the lumbar spinal cord were also performed to measure 5-HT and NA levels after systemic injection of milnacipran. Milnacipran (1-30 microg) produced dose-dependent antihypersensitivity effects. The effect lasted 6 h after the 30-microg injection. Doses of 30 microg or less produced no abnormal behavior. The peak antihypersensitivity effect of 10 microg of milnacipran was blocked by intrathecal pretreatment with antagonists of the alpha(2)-adrenoceptor (idazoxan; 30 microg) or 5-HT receptors (methysergide; 30 microg). Intrathecal pretreatment with 30 microg of naloxone, a mu-opioid receptor antagonist, did not reverse the effect of milnacipran. Isobolographic analysis indicated antinociceptive synergism between milnacipran and morphine. Microdialysis studies revealed that milnacipran increased both 5-HT and NA levels in the spinal dorsal horn. These findings suggest that the antihypersensitivity effect of intrathecal milnacipran in the postoperative pain model is monoamine-mediated. Combined administration of an SNRI with morphine might be a promising treatment to suppress postoperative hypersensitivity.

Authors+Show Affiliations

Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi, Gunma 371-8511, Japan. hobata@showa.gunma-u.ac.jpNo 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

20558774

Citation

Obata, Hideaki, et al. "Monoamine-dependent, Opioid-independent Antihypersensitivity Effects of Intrathecally Administered Milnacipran, a Serotonin Noradrenaline Reuptake Inhibitor, in a Postoperative Pain Model in Rats." The Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 3, 2010, pp. 1059-65.
Obata H, Kimura M, Nakajima K, et al. Monoamine-dependent, opioid-independent antihypersensitivity effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a postoperative pain model in rats. J Pharmacol Exp Ther. 2010;334(3):1059-65.
Obata, H., Kimura, M., Nakajima, K., Tobe, M., Nishikawa, K., & Saito, S. (2010). Monoamine-dependent, opioid-independent antihypersensitivity effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a postoperative pain model in rats. The Journal of Pharmacology and Experimental Therapeutics, 334(3), 1059-65. https://doi.org/10.1124/jpet.110.168336
Obata H, et al. Monoamine-dependent, Opioid-independent Antihypersensitivity Effects of Intrathecally Administered Milnacipran, a Serotonin Noradrenaline Reuptake Inhibitor, in a Postoperative Pain Model in Rats. J Pharmacol Exp Ther. 2010 Sep 1;334(3):1059-65. PubMed PMID: 20558774.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Monoamine-dependent, opioid-independent antihypersensitivity effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a postoperative pain model in rats. AU - Obata,Hideaki, AU - Kimura,Masafumi, AU - Nakajima,Kunie, AU - Tobe,Masaru, AU - Nishikawa,Koichi, AU - Saito,Shigeru, Y1 - 2010/06/17/ PY - 2010/6/19/entrez PY - 2010/6/19/pubmed PY - 2010/9/24/medline SP - 1059 EP - 65 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 334 IS - 3 N2 - The neurotransmitters serotonin (5-HT) and noradrenaline (NA) have important roles in suppressing nociceptive transmission in the spinal cord. In the present study, we determined the efficacy and nature of the antihypersensitivity effects of milnacipran, a 5-HT and NA reuptake inhibitor (SNRI), in the spinal cord in a rat model of postoperative pain. Sprague-Dawley rats were used in all experiments. An incision was made on the plantar aspect of the hind paw. Mechanical hypersensitivity was measured by determining the withdrawal threshold to von Frey filaments applied to the paw. Drugs were administered intrathecally 24 h after paw incision. Microdialysis studies of the dorsal horn of the lumbar spinal cord were also performed to measure 5-HT and NA levels after systemic injection of milnacipran. Milnacipran (1-30 microg) produced dose-dependent antihypersensitivity effects. The effect lasted 6 h after the 30-microg injection. Doses of 30 microg or less produced no abnormal behavior. The peak antihypersensitivity effect of 10 microg of milnacipran was blocked by intrathecal pretreatment with antagonists of the alpha(2)-adrenoceptor (idazoxan; 30 microg) or 5-HT receptors (methysergide; 30 microg). Intrathecal pretreatment with 30 microg of naloxone, a mu-opioid receptor antagonist, did not reverse the effect of milnacipran. Isobolographic analysis indicated antinociceptive synergism between milnacipran and morphine. Microdialysis studies revealed that milnacipran increased both 5-HT and NA levels in the spinal dorsal horn. These findings suggest that the antihypersensitivity effect of intrathecal milnacipran in the postoperative pain model is monoamine-mediated. Combined administration of an SNRI with morphine might be a promising treatment to suppress postoperative hypersensitivity. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20558774/Monoamine_dependent_opioid_independent_antihypersensitivity_effects_of_intrathecally_administered_milnacipran_a_serotonin_noradrenaline_reuptake_inhibitor_in_a_postoperative_pain_model_in_rats_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20558774 DB - PRIME DP - Unbound Medicine ER -