Knockdown of spinal opioid receptors by antisense targeting beta-arrestin reduces morphine tolerance and allodynia in rat.
The development of morphine tolerance and sciatic nerve injury-induced allodynia after functional knockdown of spinal opioid receptors using antisense oligonucleotides targeting beta-arrestin was investigated. Ineffectiveness of morphine in neuropathic pain suggests an implication of the same mechanism in these two processes. The development of morphine tolerance (10 microg intrathecally (i.th.), every 12 h) was significantly inhibited in rats, which received i.th. beta-arrestin antisenses (2 nM). Acute and chronic (6 days) i.th. administration of antisenses antagonized the allodynia in the rat model of neuropathic pain. Our results demonstrated that i.th. administration of beta-arrestin antisenses delayed development of tolerance to morphine and nerve injury-induced cold allodynia, which suggest that both of the investigated phenomena may be mediated by a similar mechanism, e.g. receptor desensitization. Moreover, the antisense oligonucleotides targeting beta-arrestin may constitute a new approach to the therapy of neuropathic pain.
Przewlocka
Barbara
B
Department of Molecular Neuropharmacology, Institute of Pharmacology, 12 Smetna Street, 31-343, Kraków, Poland. przebar@if-pan.krawkow.pl
Sieja
Agnieszka
A
Starowicz
Katarzyna
K
Maj
Marcin
M
Bilecki
Wiktor
W
Przewlocki
Ryszard
R
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000235:genetics*; D003080:Cold Temperature; D004361:Drug Tolerance; D006941:Hyperesthesia / Q000209:etiology / Q000503:physiopathology*; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000293:injuries; D013116:Spinal Cord / Q000378:metabolism*; D014947:Wounds and Injuries / Q000150:complications; D000071557:beta-Arrestins
D000701:Analgesics, Opioid; D019390:Arrestins; D009292:Narcotic Antagonists; D016376:Oligonucleotides, Antisense; D000071557:beta-Arrestins; D009020:Morphine