Mechanism for Increased Expression of UGT2B in the Liver of Mice with Neuropathic Pain.
Approximately 30% of patients with cancer pain experience concurrent neuropathic pain. Since these patients are not sufficiently responsive to morphine, the development of an effective method of pain relief is urgently needed. Decreased function of the μ opioid receptor, which binds to the active metabolite of morphine M-6-G in the brain, has been proposed as a mechanism for morphine resistance. Previously, we pharmacokinetically examined morphine resistance in mice with neuropathic pain, and demonstrated that the brain morphine concentration was decreased, expression level of P-glycoprotein (P-gp) in the small intestine was increased, and expression level and activity of uridine diphosphate glucuronosyltransferase (UGT)2B in the liver were increased. In order to clarify the mechanism of the increased expression of UGT2B, we examined the phase of neuropathic pain during which UGT2B expression in the liver begins to increase, and whether this increased expression is nuclear receptor-mediated. The results of this study revealed that the increased expression of UGT2B in the liver occurred during the maintenance phase of neuropathic pain, suggesting that it may be caused by transcriptional regulation which was not accompanied by increased nuclear import of pregnane X receptor (PXR).
Department of Clinical Pharmacokinetics, Hoshi University.
Mitsumasa
M
Kaneta
Wataru
W
Ochiai
Marina
M
Nagae
Wataru
W
Suto
Mika
M
Hanagata
Haruka
H
Suzuki
Satoshi
S
Kitaoka
Jo
J
Hatogai
Nobutomo
N
Ikarashi
Kiyoshi
K
Sugiyama
D000818:Animals; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics*; D006358:Hot Temperature; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000235:genetics*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D012584:Sciatic Nerve / Q000293:injuries
D000090702:Constitutive Androstane Receptor; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; C496508:Cyp3a11 protein, mouse; C517429:Cyp3a25 protein, mouse; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase