Selective inhibition of [D-ALA2, GLU4]deltrophin antinociception by supraspinal, but not spinal, administration of an antisense oligodeoxynucleotide to an opioid delta receptor

Edward J. Bilsky, Robert N. Bernstein, Gavril W. Pasternak, Victor J Hruby, Dinesh Patel, Frank Porreca, Josephine Lai

Research output: Contribution to journalArticle

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Abstract

Evidence in vivo has suggested the existence of subtypes of the δ opioid receptor (DOR), which have been termed δ1 and δ2. These proposed DOR subtypes are thought to be activated by [D-Pen2, D- Pen5]enkephalin (DPDPE, δ1) and [D-Ala2, Glu4]deltorphin (δ2). Recent work in which an antisense oligodeoxynucleotide (oligo) to a cloned DOR was administered by the intrathecal (i.th.) route has demonstrated a reduction in the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4]deltorphin, but not of [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO, μ agonist) in mice. The present investigation has extended these observations by administering the same DOR antisense oligo sequence by the intracerebroventricular (i.c.v.) route and evaluating the antinociceptive actions of i.c.v. agonist selective for δ, μ and κ receptors. I.th. treatment with DOR antisense oligo, but not mismatch oligo, significantly inhibited the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4deltorphin but not of i.th. DAMGO or U69, 593 (κ agonist), confirming previous data. In contrast, i.c.v. DOR antisense oligo, but not mismatch oligo, seletively inhibited the anitinociceptive response to i.c.v. [D-Ala2, Glu4]deltorphin without altering the antinociceptive actions of i.c.v. DPDPE, DAMGO or U69,593. The data suggest that the cloned DOR corresponds to that pharmacologically classified as δ2 and further, suggest that this δ receptor subtype may play a major role in eliciting spinal δ-mediated antinociception.

Original languageEnglish (US)
JournalLife Sciences
Volume55
Issue number2
DOIs
StatePublished - 1994

Fingerprint

delta Opioid Receptor
D-Penicillamine (2,5)-Enkephalin
Oligodeoxyribonucleotides
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Enkephalins
Opioid Receptors
deltorphin

Keywords

  • antisense oligodeoxynucleotides
  • D-Ala
  • DPDPE
  • Glu]deltorphin antinociception
  • opioid δ receptor subtypes

ASJC Scopus subject areas

  • Pharmacology

Cite this

Selective inhibition of [D-ALA2, GLU4]deltrophin antinociception by supraspinal, but not spinal, administration of an antisense oligodeoxynucleotide to an opioid delta receptor. / Bilsky, Edward J.; Bernstein, Robert N.; Pasternak, Gavril W.; Hruby, Victor J; Patel, Dinesh; Porreca, Frank; Lai, Josephine.

In: Life Sciences, Vol. 55, No. 2, 1994.

Research output: Contribution to journalArticle

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AU - Bilsky, Edward J.

AU - Bernstein, Robert N.

AU - Pasternak, Gavril W.

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AU - Patel, Dinesh

AU - Porreca, Frank

AU - Lai, Josephine

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N2 - Evidence in vivo has suggested the existence of subtypes of the δ opioid receptor (DOR), which have been termed δ1 and δ2. These proposed DOR subtypes are thought to be activated by [D-Pen2, D- Pen5]enkephalin (DPDPE, δ1) and [D-Ala2, Glu4]deltorphin (δ2). Recent work in which an antisense oligodeoxynucleotide (oligo) to a cloned DOR was administered by the intrathecal (i.th.) route has demonstrated a reduction in the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4]deltorphin, but not of [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO, μ agonist) in mice. The present investigation has extended these observations by administering the same DOR antisense oligo sequence by the intracerebroventricular (i.c.v.) route and evaluating the antinociceptive actions of i.c.v. agonist selective for δ, μ and κ receptors. I.th. treatment with DOR antisense oligo, but not mismatch oligo, significantly inhibited the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4deltorphin but not of i.th. DAMGO or U69, 593 (κ agonist), confirming previous data. In contrast, i.c.v. DOR antisense oligo, but not mismatch oligo, seletively inhibited the anitinociceptive response to i.c.v. [D-Ala2, Glu4]deltorphin without altering the antinociceptive actions of i.c.v. DPDPE, DAMGO or U69,593. The data suggest that the cloned DOR corresponds to that pharmacologically classified as δ2 and further, suggest that this δ receptor subtype may play a major role in eliciting spinal δ-mediated antinociception.

AB - Evidence in vivo has suggested the existence of subtypes of the δ opioid receptor (DOR), which have been termed δ1 and δ2. These proposed DOR subtypes are thought to be activated by [D-Pen2, D- Pen5]enkephalin (DPDPE, δ1) and [D-Ala2, Glu4]deltorphin (δ2). Recent work in which an antisense oligodeoxynucleotide (oligo) to a cloned DOR was administered by the intrathecal (i.th.) route has demonstrated a reduction in the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4]deltorphin, but not of [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO, μ agonist) in mice. The present investigation has extended these observations by administering the same DOR antisense oligo sequence by the intracerebroventricular (i.c.v.) route and evaluating the antinociceptive actions of i.c.v. agonist selective for δ, μ and κ receptors. I.th. treatment with DOR antisense oligo, but not mismatch oligo, significantly inhibited the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4deltorphin but not of i.th. DAMGO or U69, 593 (κ agonist), confirming previous data. In contrast, i.c.v. DOR antisense oligo, but not mismatch oligo, seletively inhibited the anitinociceptive response to i.c.v. [D-Ala2, Glu4]deltorphin without altering the antinociceptive actions of i.c.v. DPDPE, DAMGO or U69,593. The data suggest that the cloned DOR corresponds to that pharmacologically classified as δ2 and further, suggest that this δ receptor subtype may play a major role in eliciting spinal δ-mediated antinociception.

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