PMID- 12606628
OWN - NLM
STAT- MEDLINE
DCOM- 20030530
LR  - 20220318
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 305
IP  - 2
DP  - 2003 May
TI  - Endogenous opioid peptides contribute to antinociceptive potency of intrathecal 
      [Dmt1]DALDA.
PG  - 696-702
AB  - [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH(2); Dmt = 2',6'-dimethyltyrosine) is a 
      dermorphin analog that shows high affinity and selectivity for the mu opioid 
      receptor. The intrathecal potency of [Dmt(1)]DALDA far exceeded its affinity at 
      mu receptors and suggests that other mechanisms must be involved in its action in 
      the spinal cord. The affinity and selectivity of [Dmt(1)]DALDA was determined 
      using cell membranes expressing cloned human mu, delta, and kappa opioid 
      receptors. Competitive displacement binding with [(3)H][Dmt(1)]DALDA, [(3)H]DPDPE 
      (H-Tyr-d-Pen-Gly-Phe-d-Pen), and [(3)H]U69,593 
      [(5alpha,7alpha,8beta)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec-8-yl)-benzeneacetamide] 
      revealed K(i) of 156 +/- 26 pM for mu opioid receptor (MOR), 1.67 +/- 0.04 microM 
      for delta opioid receptor (DOR), and K(i) of 4.4 +/- 1.7 nM for kappa opioid 
      receptor (KOR), respectively. [Dmt(1)]DALDA increased guanosine 
      5'-O-(3-[(35)S]thiotriphosphate) binding in MOR, DOR, and KOR membranes, with 
      EC(50) being 17 (8.8-33) nM, 2 (1.2-3.2) microM, and 124 (15-1000) nM, 
      respectively. Intrathecal [Dmt(1)]DALDA inhibited the tail-flick response in mice 
      with ED(50) = 1.22 (0.59-2.34) pmol. Intrathecal administration of an antiserum 
      against dynorphin A(1-17) or [Met(5)]enkephalin significantly attenuated the 
      response to i.t. [Dmt(1)]DALDA, resulting in ED(50) of 6.2 (3.6-12.6) pmol and 
      6.6 (3.5-19.6) pmol, respectively. Neither antisera had any effect on the 
      response to i.t. morphine. Intracerebroventricular (i.c.v.) [Dmt(1)]DALDA was not 
      affected by previous i.c.v. administration of anti-Dyn or anti-ME. Pretreatment 
      with norbinaltorphimine or naltriben also attenuated the antinociceptive response 
      to i.t., but not i.c.v., [Dmt(1)]DALDA. These data suggest that i.t. 
      [Dmt(1)]DALDA causes the release of dynorphin and [Met(5)]enkephalin-like 
      substances that act at kappa and delta receptors, respectively, to contribute to 
      the extraordinary potency of [Dmt(1)]DALDA.
FAU - Szeto, Hazel H
AU  - Szeto HH
AD  - Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell 
      University, 1300 York Avenue, New York, NY 10021, USA. hhszeto@med.cornell.edu
FAU - Soong, Yi
AU  - Soong Y
FAU - Wu, Dunli
AU  - Wu D
FAU - Qian, XuanXuan
AU  - Qian X
FAU - Zhao, Guo-Min
AU  - Zhao GM
LA  - eng
GR  - P01 DA08924/DA/NIDA NIH HHS/United States
GR  - R37-DA02475/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030124
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide)
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Antibodies, Blocking)
RN  - 0 (Endorphins)
RN  - 0 (Narcotic Antagonists)
RN  - 0 (Oligopeptides)
RN  - 0 (Receptors, Opioid, delta)
RN  - 0 (Receptors, Opioid, kappa)
RN  - 0 (Receptors, Opioid, mu)
RN  - 36B82AMQ7N (Naloxone)
RN  - 36OOQ86QM1 (norbinaltorphimine)
RN  - 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
RN  - 58569-55-4 (Enkephalin, Methionine)
RN  - 5S6W795CQM (Naltrexone)
RN  - 74913-18-1 (Dynorphins)
RN  - 82824-01-9 (naloxonazine)
SB  - IM
MH  - Analgesics, Opioid/administration & dosage/*pharmacology
MH  - Animals
MH  - Antibodies, Blocking/pharmacology
MH  - Cloning, Molecular
MH  - Dynorphins/antagonists & inhibitors/immunology/physiology
MH  - Endorphins/*physiology
MH  - Enkephalin, Methionine/antagonists & inhibitors/immunology/physiology
MH  - Guanosine 5'-O-(3-Thiotriphosphate)/metabolism
MH  - Hot Temperature
MH  - Injections, Intraventricular
MH  - Injections, Spinal
MH  - Male
MH  - Mice
MH  - Naloxone/*analogs & derivatives/pharmacology
MH  - Naltrexone/*analogs & derivatives/pharmacology
MH  - Narcotic Antagonists/pharmacology
MH  - Oligopeptides/administration & dosage/*pharmacology
MH  - Pain Measurement/drug effects
MH  - Radioligand Assay
MH  - Reaction Time
MH  - Receptors, Opioid, delta/drug effects
MH  - Receptors, Opioid, kappa/drug effects
MH  - Receptors, Opioid, mu/drug effects
EDAT- 2003/02/28 04:00
MHDA- 2003/05/31 05:00
CRDT- 2003/02/28 04:00
PHST- 2003/02/28 04:00 [pubmed]
PHST- 2003/05/31 05:00 [medline]
PHST- 2003/02/28 04:00 [entrez]
AID - jpet.102.048561 [pii]
AID - 10.1124/jpet.102.048561 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2003 May;305(2):696-702. doi: 10.1124/jpet.102.048561. Epub 
      2003 Jan 24.