Abstract
The recently isolated peptides endomorphin-1 and endomorphin-2 have been suggested to be the endogenous ligands for the mureceptor. In traditional opioid receptor binding assays in mouse brain homogenates, both endomorphin-1 and endomorphin-2 competed bothmu1 and mu2receptor sites quite potently. Neither compound had appreciable affinity for either delta orkappa1 receptors, confirming an earlier report. However, the two endomorphins displayed reasonable affinities for kappa3 binding sites, withKi values between 20 and 30 nM. Both endomorphins competed3H-[d-Ala2,MePhe4,Gly(ol)5] enkephalin binding to MOR-1 receptors expressed in CHO cells with high affinity. In mouse brain homogenates 125I-endomorphin-1 and125I-endomorphin-2 binding was selectively competed by mu ligands. 125I-Endomorphin-1 and125I-endomorphin-2 also labeled MOR-1 receptors expressed in CHO cells with high affinity. Autoradiography of the two125I-labeled endomorphins demonstrated regional patterns in the brain similar to those previously observed for mudrugs. Pharmacologically, the endomorphins were potent analgesics. Although they were equipotent supraspinally, endomorphin-1 was more potent spinally. Endomorphin analgesia was effectively blocked by naloxone, as well as the mu-selective antagonists β-funaltrexamine and naloxonazine. In CXBK mice, which are insensitive to supraspinal morphine, neither endomorphin was active, consistent with a mu mechanism of action. Finally, the endomorphins inhibited gastrointestinal transit. In conclusion, these results support the mu selectivity of these agents.
Footnotes
-
Send reprint requests to: Dr. Gavril W. Pasternak, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.
-
↵1 This work was supported, in part, by grants DA02615 and DA07242 from the National Institute on Drug Abuse to G.W.P. and a core grant from the National Cancer Institute to Memorial Sloan-Kettering Cancer Center. G.C.R. was supported by Mentored Scientist Award DA00310, G.W.P. was supported by Research Scientist Award DA00220 from the National Institute on Drug Abuse and S.L. was supported by Training Grant CA09461 from the National Cancer Institute.
- Abbreviations:
- β-FNA
- β-funaltrexamine
- i.c.v.
- intracerebroventricularly
- MeONtx
- 3-methoxynaltrexone
- CHO
- Chinese hamster ovary
- TFA
- trifluoroacetic acid
- DAMGO
- [d-Ala2, MePhe4, Gly (01)5]enkephalin
- Received January 21, 1998.
- Accepted April 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|