N-methyl-D-aspartate receptors mediate endogenous opioid release in enteric neurons after abdominal surgery.
OBJECTIVE
We tested the hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate surgery-induced opioid release in enteric neurons.


METHODS
We used mu opioid receptor (muOR) internalization as a measure of opioid release with immunohistochemistry and confocal microscopy. MuOR internalization was quantified in enteric neurons from nondenervated and denervated ileal segments of guinea pig after abdominal laparotomy with and without pretreatment with NMDA-receptor antagonists acting at different recognition sites (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,b] cyclohepten-5,10-imine (MK-801) or (D) 2-amino-5-phosphopenoic acid (AP-5) at .5, 1 mg/kg; 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazinol [4,5-]quinoline-5-oxide choline (MRZ 2/576) or 8-chloro-1,4-dioxo-1,2,3,4-tetrahydropyridazinol [4,5-]quinoline choline salt (MRZ 2/596) at .3, 1 mg/kg, or with an antagonist for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (1, 3 mg/kg). To determine whether NMDA stimulation induces opioid release, (1) ilea were exposed to NMDA (100 micromol/L) and D-serine (10 micromol/L) with or without the antagonist MK-801 or AP-5 (50 micromol/L); and (2) neuromuscular preparations of the ileum were stimulated electrically (20 Hz, 20 min) with or without MK-801 or AP-5 (50 micromol/L).


RESULTS
MuOR endocytosis induced by abdominal laparotomy was inhibited significantly by NMDA-receptor antagonists in nondenervated and denervated ileal segments, but not by the AMPA-receptor antagonist. MuOR endocytosis in neurons exposed to NMDA or electrical stimulation was prevented by NMDA-R antagonists.


CONCLUSIONS
Abdominal laparotomy evokes local release of glutamate that results in endogenous opioid release through the activation of peripheral NMDA receptors. This suggests an interaction between the glutamatergic and opioid systems in response to the noxious and perhaps mechanosensory stimulation of surgery.
Patierno
Simona
S
CURE Digestive Diseases Research Center, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, 90073, USA. kira@ucla.edu
Zellalem
Wubanche
W
Ho
Anthony
A
Parsons
Chris G
CG
Lloyd
K C Kent
KC
Tonini
Marcello
M
Sternini
Catia
C
D000818:Animals; D013505:Digestive System Surgical Procedures; D016291:Dizocilpine Maleate / Q000494:pharmacology; D017615:Enteric Nervous System / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000502:physiology; D007150:Immunohistochemistry; D007813:Laparotomy; D008297:Male; D018613:Microscopy, Confocal; D009294:Narcotics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D018698:Glutamic Acid; D016291:Dizocilpine Maleate