Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats.
Morphine has been used in previous studies that investigate interactions between the spinal cord mu-opioid and N-methyl-D-aspartate (NMDA) receptors in mechanisms of antinociceptive tolerance. Although morphine acts primarily on the mu-receptor, it also activates other subtypes of opioid receptors. In the present study, the selective mu-opioid agonist, D-Ala2-N-Me-Phe4,Gly-ol5-enkephalin (DAMGO), was used to further test the hypothesis. Repeated intrathecal (i.t.) administration of 6 microg DAMGO (twice daily) in rats for 7 days resulted in an approximately 17-fold rightward shift of the cumulative dose-response curve (the tail-flick test) on Day 8 compared to that on Day 1. This rightward shift of the dose-response curve was prevented by the i.t. co-administration with DAMGO of the NMDA receptor antagonist MK-801 (10 = 5 > 2.5 >> 1.25 nmol > saline). Further, a lower dose range of MK-801 (2.5 > 1.25 nmol > 0.625 > 0.313 = saline) was effective to prevent the antinociceptive tolerance to a lower dose (1.5 microg) of DAMGO using the same i.t. administration regimen. Thus, the present results provide further evidence supporting a cellular and intracellular model of opioid tolerance involving interactions between the mu-opioid and the NMDA receptors in the spinal cord.
Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
J
J
Mao
D D
DD
Price
J
J
Lu
D J
DJ
Mayer
D000700:Analgesics / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000187:drug effects* / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000187:drug effects*
D000700:Analgesics; D004745:Enkephalins; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016291:Dizocilpine Maleate