Knockdown of spinal opioid receptors by antisense targeting β-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 β-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 μg intrathecally (i.th.), every 12 h) was significantly inhibited in rats, which received i.th. β-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 β-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 β-arrestin may constitute a new approach to the therapy of neuropathic pain.