Chronic effect of [D-Pen2,D-Pen5]enkephalin on rat brain opioid receptors

Tao Pao-Luh, Tsai Chiu-Lan, Chang Li-Ren, Horace H. Loh

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21 Scopus citations


In previous studies, we have demonstrated that chronic etorphine or [D-Ala2,D-Leu5]enkephalin (DADLE) treatment of rats results in the reduction of μ- and δ-opioid receptor binding activities as tolerance develops. As both etorphine and DADLE are relatively non-specific opioid ligands, interacting with both μ- and δ-rcceptors these studies could not determine whether down-regulation of a specific receptor type occurs. Therefore, in the present studies, animals were rendered tolerant to the δ-opioid receptor-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), and receptor binding activities were measured. Treating Sprague-Dawley rats with increasing doses of DPDPE (80-160-240-320 μg/kg) i.c.v. for 1 to 4 days resulted in a time-dependent increase in the ad50 of DPDPE to elicit an antinociceptivc response. When δ-receptor binding was determined by using [3H]DPDPE, a 40-50% decrease in binding in the midbrain and cortex, and 25-35% decrease in binding in the striatum were observed after 3 or 4 days of DPDPE treatment. Scatchard analysis of the [3H]DPDPE saturation binding data revealed a decrease in Bmax values and no significant change in kd values. To our surprise, when μ-receptor hinding was determined by using (3H]Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO), a 10-15% decrease in binding was also observed in the midbrain and cortex after 4 days of DPDPE treatment. Our conclusion is that chronic DPDPE treatment preferentially reduces δ-opioid receptor binding activity. Its minor effect on the μ-opioid receptor maybe due to an interaction between δex and μex binding sites.

Original languageEnglish (US)
Pages (from-to)209-214
Number of pages6
JournalEuropean Journal of Pharmacology
Issue number2-3
StatePublished - Aug 29 1991

Bibliographical note

Funding Information:
The present studies were supported by a Grant NSC 77-ll412-8016-33 from the National Science Council. Taipei, Taiwan. Republic of China. H.H. Loh is the recipient of a National Institute of Drug Abuse Career Award K-02-DA-70554.


  • (Rat)
  • DPDPE ([D-Pen.D-Pen]enkephalin)
  • Opioid receptors
  • Tolerance


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