The Use of Antisense Oligodeoxynucleotides to Block the Spinal Effects of κ1 Agonist-Induced Antinociception in the Mouse

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Abstract
Previous workers have shown that an antisense oligodeoxynucleotide (oligo) to κ-opioid receptor mRNA blocks κ receptor-mediated antinociception in the spinal cord of male ICR mice. The present study confirms these findings using an oligo to a different fragment of the κ 1 receptor and a different protocol for its administration. In addition, the study extended the previous work by showing an effect of the κ 1 antisense on the antinociception produced by β-endorphin. The tail flick response was used for the antinociceptive test. Intrathecal (i.t.) pretreatment of mice with the antisense oligo (156 pmol) for 1 to 4 days once a day caused a time-dependent blockade of the antinociception induced by U50,488H, an κ 1-opioid receptor agonist. The antinociception remained blocked for at least 5 days and recovered in 9 to 14 days after ceasing the treatment of antisense oligo. Antisense oligo at doses from 15.6 to 468 pmol given i.t. once a day for 4 days dose-dependently attenuated the antinociception induced by i.t.-administered U50,488H. However, the antinociception induced by Mr 2033 or bremazocine, κ 2-opioid receptor agonists, DAMGO ([d-Ala2-MePhe4-Gly(ol)5]enkephalin), a μ-opioid receptor agonist, or [d-Ala2]deltorphin II, a δ 2-opioid receptor agonist, was not affected. However, the antinociception induced by β-endorphin given i.t. was attenuated. Mismatch oligo (156 pmol) was ineffective against the antinociception induced by U50,488H, Mr 2033, bremazocine, DAMGO, β-endorphin, or [d-Ala2]deltorphin II. The studies confirm previous pharmacological studies at the molecular level indicating a distinct κ 1-opioid receptor for antinociception in the spinal cord.

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