Inhibition of MPEP on the development of morphine antinociceptive tolerance and the biosynthesis of neuronal nitric oxide synthase in rat spinal cord.
We evaluated the ability of spinally administered 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), and 2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, to modulate the antinociceptive action and tolerance of intrathecal (i.t.) morphine infusion in rats, and assessed the expression of spinal nitric oxide synthase (NOS). MPEP co-infused with morphine not only preserved the analgesia and retarded the development of antinociceptive tolerance, but also partially inhibited the up-regulation of spinal nNOS protein. However, the loss of morphine antinociceptive effect and tolerance were accelerated when CHPG and morphine were co-infused, while spinal nNOS activity was significantly up-regulated. We hypothesize that activation of mGluR5 and NMDA receptors occurs after the appearance of antinociceptive tolerance to morphine. The activation of these receptors might stimulate an increased concentration of intracellular calcium and activation of PKC, which both play a vital role in the development of morphine antinociceptive tolerance and expression of spinal NOS. The synergistic effect which seems to exist between mGluRs and iGluRs may also contribute to this phenomenon.
Xu
Tao
T
Department of Anesthesiology, The Sixth Affiliated People's Hospital, Shanghai Jiaotong University, 600 Yi Shan Road, Shanghai 200233, China.
Jiang
Wei
W
Du
Dongping
D
Xu
Yongming
Y
Zhou
Quanhong
Q
Pan
Xiaorong
X
Lou
Yejiang
Y
Xu
Liang
L
Ma
Ke
K
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D009294:Narcotics / Q000008:administration & dosage*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010648:Phenylacetates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors
C107349:2-chloro-5-hydroxyphenylglycine; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D010648:Phenylacetates; D011725:Pyridines; D009020:Morphine; C121465:6-methyl-2-(phenylethynyl)pyridine; D052248:Nitric Oxide Synthase Type I; D005998:Glycine