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Supraspinal antinociceptive response to [D-Pen(2,5)]-enkephalin (DPDPE) is pharmacologically distinct from that to other delta-agonists in the rat.
J Pharmacol Exp Ther. 2000 Dec; 295(3):1135-41.JP

Abstract

The cloned delta-opioid receptor (DOR) is being investigated as a potential target for novel analgesics with an improved safety profile over mu-opioid receptor agonists such as morphine. The current study used antisense techniques to evaluate the role of DOR in mediating supraspinal antinociception in rats. All of the opioid agonists tested (delta-selective: deltorphin II, DPDPE, pCl-DPDPE, SNC80; mu-selective: DAMGO; i.c.v.) provided significant, dose-dependent antinociception in the paw pressure assay. Administration of a phosphodiester antisense oligonucleotide (i.c.v.) targeted against DOR inhibited antinociception in response to SNC80, deltorphin II, and pCl-DPDPE compared with mismatch and saline-treated controls. However, antisense treatment did not inhibit the response to DPDPE or DAMGO. In contrast, the highly selective mu-antagonist CTOP blocked antinociception in response to ED(80) concentrations of DAMGO and DPDPE, reduced the response to pCl-DPDPE, and did not alter the response to deltorphin II or SNC80. In total, these data suggest that DOR mediates the antinociceptive response to deltorphin II, SNC80, and pCl-DPDPE at supraspinal sites and further demonstrates that the DOR-mediated response to deltorphin II and SNC80 is independent of mu-receptor activation. Conversely, supraspinal antinociception in response to DPDPE is mediated by a receptor distinct from DOR; this response is directly or indirectly sensitive to mu-receptor blockade. The distinct pharmacological profile of DPDPE suggests that either this prototypical delta-agonist mediates antinociception by a direct, nonselective interaction at mu-receptors or DPDPE interacts with a novel delta-subtype that, in turn, indirectly activates mu-receptors in the brain.

Authors+Show Affiliations

AstraZeneca R & D Montréal, Québec, Canada. glf@viron.on.caNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11082450

Citation

Fraser, G L., et al. "Supraspinal Antinociceptive Response to [D-Pen(2,5)]-enkephalin (DPDPE) Is Pharmacologically Distinct From That to Other Delta-agonists in the Rat." The Journal of Pharmacology and Experimental Therapeutics, vol. 295, no. 3, 2000, pp. 1135-41.
Fraser GL, Pradhan AA, Clarke PB, et al. Supraspinal antinociceptive response to [D-Pen(2,5)]-enkephalin (DPDPE) is pharmacologically distinct from that to other delta-agonists in the rat. J Pharmacol Exp Ther. 2000;295(3):1135-41.
Fraser, G. L., Pradhan, A. A., Clarke, P. B., & Wahlestedt, C. (2000). Supraspinal antinociceptive response to [D-Pen(2,5)]-enkephalin (DPDPE) is pharmacologically distinct from that to other delta-agonists in the rat. The Journal of Pharmacology and Experimental Therapeutics, 295(3), 1135-41.
Fraser GL, et al. Supraspinal Antinociceptive Response to [D-Pen(2,5)]-enkephalin (DPDPE) Is Pharmacologically Distinct From That to Other Delta-agonists in the Rat. J Pharmacol Exp Ther. 2000;295(3):1135-41. PubMed PMID: 11082450.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Supraspinal antinociceptive response to [D-Pen(2,5)]-enkephalin (DPDPE) is pharmacologically distinct from that to other delta-agonists in the rat. AU - Fraser,G L, AU - Pradhan,A A, AU - Clarke,P B, AU - Wahlestedt,C, PY - 2000/11/18/pubmed PY - 2001/2/28/medline PY - 2000/11/18/entrez SP - 1135 EP - 41 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 295 IS - 3 N2 - The cloned delta-opioid receptor (DOR) is being investigated as a potential target for novel analgesics with an improved safety profile over mu-opioid receptor agonists such as morphine. The current study used antisense techniques to evaluate the role of DOR in mediating supraspinal antinociception in rats. All of the opioid agonists tested (delta-selective: deltorphin II, DPDPE, pCl-DPDPE, SNC80; mu-selective: DAMGO; i.c.v.) provided significant, dose-dependent antinociception in the paw pressure assay. Administration of a phosphodiester antisense oligonucleotide (i.c.v.) targeted against DOR inhibited antinociception in response to SNC80, deltorphin II, and pCl-DPDPE compared with mismatch and saline-treated controls. However, antisense treatment did not inhibit the response to DPDPE or DAMGO. In contrast, the highly selective mu-antagonist CTOP blocked antinociception in response to ED(80) concentrations of DAMGO and DPDPE, reduced the response to pCl-DPDPE, and did not alter the response to deltorphin II or SNC80. In total, these data suggest that DOR mediates the antinociceptive response to deltorphin II, SNC80, and pCl-DPDPE at supraspinal sites and further demonstrates that the DOR-mediated response to deltorphin II and SNC80 is independent of mu-receptor activation. Conversely, supraspinal antinociception in response to DPDPE is mediated by a receptor distinct from DOR; this response is directly or indirectly sensitive to mu-receptor blockade. The distinct pharmacological profile of DPDPE suggests that either this prototypical delta-agonist mediates antinociception by a direct, nonselective interaction at mu-receptors or DPDPE interacts with a novel delta-subtype that, in turn, indirectly activates mu-receptors in the brain. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11082450/Supraspinal_antinociceptive_response_to_[D_Pen_25_]_enkephalin__DPDPE__is_pharmacologically_distinct_from_that_to_other_delta_agonists_in_the_rat_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11082450 DB - PRIME DP - Unbound Medicine ER -