The effect of morphine on formalin-evoked behaviour and spinal release of excitatory amino acids and prostaglandin E2 using microdialysis in conscious rats.
1. In the present study, the object was to examine the effects of morphine on spinal release in vivo of excitatory amino acids (EAA), prostaglandin E2 (PGE2), and a marker for nitric oxide (NO) synthesis, citrulline (Cit), evoked by a protracted noxious stimulus produced by the injection of formalin into the paw. Spinal release was monitored in conscious rats using a microdialysis probe implanted into the subarachnoid space with the active site placed at the level of the lumbar enlargement. In split dialysate samples. EAAs were measured by high performance liquid chromatography (h.p.l.c.) and PGE2 was determined by radioimmunoassay. 2. Resting concentrations in nmol ml-1 for the amino acids (mean +/- s.e.mean, n = 21) were: 4.8 +/- 0.4 for glutamate (Glu), 0.8 +/- 0.1 for aspartate (Asp), 8.8 +/- 0.8 for taurine (Tau), 24 +/- 3 for glycine (Gly), 19 +/- 3 for serine (Ser), 5.2 +/- 0.8 for asparagine (Asn), 64 +/- 4 for glutamine (Gln) and 5.2 +/- 0.4 for Cit. Mean basal release for PGE2 was 12 +/- 1 pmol ml-1. 3. Subcutaneous (s.c.) injection of 5% formalin evoked a biphasic flinching behaviour (phase 1: 0-9 min and phase 2: 10-60 min) of the injected paw. Corresponding to phase 1 behaviour, there was a significant increase (50-100%) in spinal levels of Glu, Asp, Tau, Gly, Cit and PGE2, but not Ser, Asn and Gln. A significant (P < 0.01) second phase increase in release was observed only for Cit and PGE2. However, Glu and Asp levels were increased by approximately 45%. 4. Injection of morphine sulphate (3 mg kg-1, s.c.) had no effect on resting release, but produced a significant suppression of the formalin-evoked behaviour and release of Glu, Asp, Tau, Gly, Cit and PGE2. The effect of morphine was reversed by pretreatment with 1 mg kg-1 naloxone. Naloxone by itself did not change the release or behaviour of the formalin test.5. This study demonstrates that both spinal EAA and PGE2 release patterns correlate with behavioural nociceptive responses in the formalin test and that morphine suppresses the formalin-evoked behaviours and spinal release. The reversal by naloxone of the morphine effect indicates mediation via an opioid receptor.
Malmberg
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Department of Anaesthesiology, University of California, San Diego, La Jolla 92093, USA.
Yaksh
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TL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002956:Citrulline / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D018846:Excitatory Amino Acids / Q000378:metabolism*; D005557:Formaldehyde; D008297:Male; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D018846:Excitatory Amino Acids; D005557:Formaldehyde; D002956:Citrulline; D009270:Naloxone; D009020:Morphine; D015232:Dinoprostone