Antagonism of δ2-opioid receptors by naltrindole-5'-isothiocyanate attenuates heroin self-administration but not antinociception in rats

T. J. Martin, S. A. Kim, D. G. Cannon, G. M. Sizemore, D. Bian, Frank Porreca, J. E. Smith

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

δ-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of δ-opioid receptors in vivo. This experiment assessed the contribution of δ-opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible δ-antagonist naltrindole-5'-isothiocyanate (5'-NTII) were evaluated on heroin self-administration and hot-plate antinociception in rats. 5'-NTII (10 nmol i.c.v.) shifted the dose-response curve for heroin self-administration downward, increasing the A50 values on the ascending and descending limbs by approximately 0.5 log units and decreasing the maximum by 33%. 5'-NTII (40 nmol i.c.v.) shifted both limbs of the heroin self-administration dose-effect curve 1.2 log units to the right and decreased the maximum by 90%. Heroin self-administration gradually returned to baseline levels over 7 or 17 days after administration of 10 or 40 nmol 5'-NTII, respectively. 5'-NTII (40 nmol i.c.v.) decreased the self-administration of 0.17 mg/infusion cocaine by 40% while having no effect on responding maintained by 0.33 or 0.67 mg/infusion. 5'-NTII attenuated the antinociceptive effects of deltorphin (δ2) in a dose-dependent manner while having no effect on antinociception elicited after i.c.v, administration of [D-Pen2,D-Pen5]-enkephalin (δ1) or [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (μ). In addition, the antinociceptive effects of heroin were not significantly affected by 5'-NTII (40 nmol i.c.v.). Therefore, 5'-NTII can attenuate the reinforcing effects of heroin at doses that do not affect its antinociceptive effects. Long-acting δ2-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.

Original languageEnglish (US)
Pages (from-to)975-982
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume294
Issue number3
StatePublished - 2000
Externally publishedYes

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Self Administration
Heroin
Opioid Receptors
Extremities
D-Penicillamine (2,5)-Enkephalin
Heroin Dependence
Narcotic Antagonists
Enkephalins
naltrindole 5'-isothiocyanate
Cocaine
Opioid Analgesics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Antagonism of δ2-opioid receptors by naltrindole-5'-isothiocyanate attenuates heroin self-administration but not antinociception in rats. / Martin, T. J.; Kim, S. A.; Cannon, D. G.; Sizemore, G. M.; Bian, D.; Porreca, Frank; Smith, J. E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 294, No. 3, 2000, p. 975-982.

Research output: Contribution to journalArticle

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title = "Antagonism of δ2-opioid receptors by naltrindole-5'-isothiocyanate attenuates heroin self-administration but not antinociception in rats",
abstract = "δ-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of δ-opioid receptors in vivo. This experiment assessed the contribution of δ-opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible δ-antagonist naltrindole-5'-isothiocyanate (5'-NTII) were evaluated on heroin self-administration and hot-plate antinociception in rats. 5'-NTII (10 nmol i.c.v.) shifted the dose-response curve for heroin self-administration downward, increasing the A50 values on the ascending and descending limbs by approximately 0.5 log units and decreasing the maximum by 33{\%}. 5'-NTII (40 nmol i.c.v.) shifted both limbs of the heroin self-administration dose-effect curve 1.2 log units to the right and decreased the maximum by 90{\%}. Heroin self-administration gradually returned to baseline levels over 7 or 17 days after administration of 10 or 40 nmol 5'-NTII, respectively. 5'-NTII (40 nmol i.c.v.) decreased the self-administration of 0.17 mg/infusion cocaine by 40{\%} while having no effect on responding maintained by 0.33 or 0.67 mg/infusion. 5'-NTII attenuated the antinociceptive effects of deltorphin (δ2) in a dose-dependent manner while having no effect on antinociception elicited after i.c.v, administration of [D-Pen2,D-Pen5]-enkephalin (δ1) or [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (μ). In addition, the antinociceptive effects of heroin were not significantly affected by 5'-NTII (40 nmol i.c.v.). Therefore, 5'-NTII can attenuate the reinforcing effects of heroin at doses that do not affect its antinociceptive effects. Long-acting δ2-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.",
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T1 - Antagonism of δ2-opioid receptors by naltrindole-5'-isothiocyanate attenuates heroin self-administration but not antinociception in rats

AU - Martin, T. J.

AU - Kim, S. A.

AU - Cannon, D. G.

AU - Sizemore, G. M.

AU - Bian, D.

AU - Porreca, Frank

AU - Smith, J. E.

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N2 - δ-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of δ-opioid receptors in vivo. This experiment assessed the contribution of δ-opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible δ-antagonist naltrindole-5'-isothiocyanate (5'-NTII) were evaluated on heroin self-administration and hot-plate antinociception in rats. 5'-NTII (10 nmol i.c.v.) shifted the dose-response curve for heroin self-administration downward, increasing the A50 values on the ascending and descending limbs by approximately 0.5 log units and decreasing the maximum by 33%. 5'-NTII (40 nmol i.c.v.) shifted both limbs of the heroin self-administration dose-effect curve 1.2 log units to the right and decreased the maximum by 90%. Heroin self-administration gradually returned to baseline levels over 7 or 17 days after administration of 10 or 40 nmol 5'-NTII, respectively. 5'-NTII (40 nmol i.c.v.) decreased the self-administration of 0.17 mg/infusion cocaine by 40% while having no effect on responding maintained by 0.33 or 0.67 mg/infusion. 5'-NTII attenuated the antinociceptive effects of deltorphin (δ2) in a dose-dependent manner while having no effect on antinociception elicited after i.c.v, administration of [D-Pen2,D-Pen5]-enkephalin (δ1) or [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (μ). In addition, the antinociceptive effects of heroin were not significantly affected by 5'-NTII (40 nmol i.c.v.). Therefore, 5'-NTII can attenuate the reinforcing effects of heroin at doses that do not affect its antinociceptive effects. Long-acting δ2-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.

AB - δ-Opioid receptors have been implicated in reinforcement processes and antagonists are available that produce long-lasting and selective antagonism of δ-opioid receptors in vivo. This experiment assessed the contribution of δ-opioid receptors to the antinociceptive and reinforcing properties of heroin. The effects of the irreversible δ-antagonist naltrindole-5'-isothiocyanate (5'-NTII) were evaluated on heroin self-administration and hot-plate antinociception in rats. 5'-NTII (10 nmol i.c.v.) shifted the dose-response curve for heroin self-administration downward, increasing the A50 values on the ascending and descending limbs by approximately 0.5 log units and decreasing the maximum by 33%. 5'-NTII (40 nmol i.c.v.) shifted both limbs of the heroin self-administration dose-effect curve 1.2 log units to the right and decreased the maximum by 90%. Heroin self-administration gradually returned to baseline levels over 7 or 17 days after administration of 10 or 40 nmol 5'-NTII, respectively. 5'-NTII (40 nmol i.c.v.) decreased the self-administration of 0.17 mg/infusion cocaine by 40% while having no effect on responding maintained by 0.33 or 0.67 mg/infusion. 5'-NTII attenuated the antinociceptive effects of deltorphin (δ2) in a dose-dependent manner while having no effect on antinociception elicited after i.c.v, administration of [D-Pen2,D-Pen5]-enkephalin (δ1) or [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (μ). In addition, the antinociceptive effects of heroin were not significantly affected by 5'-NTII (40 nmol i.c.v.). Therefore, 5'-NTII can attenuate the reinforcing effects of heroin at doses that do not affect its antinociceptive effects. Long-acting δ2-opioid antagonists may be beneficial in the treatment of heroin dependence or as adjuncts to reduce the abuse liability of opioid analgesics.

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