TY - JOUR
T1 - Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective μ or δ opioid agonists in mice
AU - Bilsky, Edward J.
AU - Inturrisi, Charles E.
AU - Sadée, Wolfgang
AU - Hruby, Victor J.
AU - Porreca, Frank
N1 - Funding Information:
This work was supported by USPHS Grants from the NIDA. F.P. and C.E.I. are recipients of Research Scientist Awards from the NIDA (DA 00185 and DA00198, respectively). The authors thank Drs. Paul Ornstein and Dennis Zimmerman of Lilly Research Laboratories for the LY235959 compound. Morphine, DAMGO and PL017 were obtained through the National Institute of Drug Abuse Drug Supply Program. We thank Dr. Ron Haaseth for the synthesis and purification of [ d -Ala 2 , Glu 4 ]deltorphin.
PY - 1996/12
Y1 - 1996/12
N2 - N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (μ) and delta (δ) agonists, however, has not been reported. In these experiments, selective μ and δ receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of μ agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a δ agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a δ-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective μ and δ opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.
AB - N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (μ) and delta (δ) agonists, however, has not been reported. In these experiments, selective μ and δ receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of μ agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a δ agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a δ-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective μ and δ opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.
KW - LY235959
KW - MK801
KW - N-methyl-D-aspartate antagonists
KW - antinociceptive tolerance
KW - mice
KW - opioids
KW - swim-stress
KW - δ receptors
KW - μ receptors
UR - http://www.scopus.com/inward/record.url?scp=0030444685&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030444685&partnerID=8YFLogxK
U2 - 10.1016/S0304-3959(96)03185-5
DO - 10.1016/S0304-3959(96)03185-5
M3 - Article
C2 - 9121809
AN - SCOPUS:0030444685
SN - 0304-3959
VL - 68
SP - 229
EP - 237
JO - Pain
JF - Pain
IS - 2-3
ER -