Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats.
Excitatory amino acids (EAAs) are involved in the development of opioid tolerance. The present study reveals that an increasing of CSF EAAs concentration might be responsible for the losing of morphine's antinociceptive effect in morphine tolerant rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters and one microdialysis probe, then continuously infused i.t. for 5 days with saline (1 microl/h; control group), morphine (15 micrograms/h), the NMDA antagonist, MK-801 (5 micrograms/h), or morphine (15 micrograms/h) plus MK-801 (5 micrograms/h). Each day, tail-flick responses were measured; in addition, CSF dialysates were collected and CSF amino acids measured by high performance liquid chromatography using a fluorescence detector. Morphine started to lose its analgesic effect on day 2 and this effect was overcome by MK-801. The AD(50) (AD: analgesic dose) was 1.33 micrograms in control animals, 83.83 micrograms in morphine-tolerant rats (a 63-fold shift), and 11.2 micrograms (a 8.4-fold shift) in rats that had received MK-801 plus morphine. No significant differences were observed in CSF amino acid release between the groups from day 1 to day 5. On day 5, after basal dialysate collection, a 10-micrograms challenge of morphine was administered i.t., and CSF samples collected over the next 3 h. After morphine challenge, morphine-tolerant rats showed a significant increase in the release of glutamate and aspartate (131+/-9.5% and 156+/-12% of basal levels, respectively), and no antinociceptive effect in the tail-flick latency test, while MK-801/morphine co-infused rats showed no increase in morphine-induced EAA release and a partial antinociceptive effect (MPE=40%). The present study provides direct evidence for a relationship between EAA release and a lack of an antinociceptive response to morphine, and shows that the NMDA antagonist, MK-801, attenuates both of these effects.
Wen
Zhi Hong
ZH
Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, #325, Chenggung Road, Section 2, Neihu 114, Taipei, Taiwan.
Chang
Yi Chen
YC
Cherng
Chen Hwan
CH
Wang
Jhi Joung
JJ
Tao
Pao Luh
PL
Wong
Chih Shung
CS
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000134:cerebrospinal fluid; D002851:Chromatography, High Pressure Liquid; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000134:cerebrospinal fluid*; D018698:Glutamic Acid / Q000134:cerebrospinal fluid; D007278:Injections, Spinal; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D001224:Aspartic Acid; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D009020:Morphine