Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study

Abstract

1 The effect of morphine (10 mg kg-', s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF).2 The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3 The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4 The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cma, and AUCO4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5 At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

“…For example, potentiated startle during withdrawal is relieved by a second drug exposure or administration of anxiolytic compounds (Harris and Gewirtz, 2004;Rothwell et al, 2009;Engelmann et al, 2009, Radke et al, 2011. The timing of the withdrawal-potentiated startle effect following morphine also coincides with the decrease in drug levels in the brain (Barjavel et al, 1995;Hipps et al, 1976).…”

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

“…However, several pieces of evidence argue against this interpretation. First, M3G levels in plasma and CSF are higher at 2 hr after injection of 10-15 mg/kg of morphine (Barjavel et al, 1995;Shang et al, 2006) than they are at 4 hr post-injection, yet the anxiolytic-like effects observed after acute administration of 10 mg/kg morphine peaked at 4 hr, and were absent at 2 hr. Second, the lower dose of morphine (5.6 mg/kg) produces anxiolytic-like effects at 2 hr post-treatment where the higher dose of 10 mg/kg is without effect, yet plasma levels of M3G at 2 hr post-injection are significantly higher with 10 mg/kg than 5.6 mg/kg of morphine (Barjavel et al, 1995;Zheng et al, 1998).…”

“…First, M3G levels in plasma and CSF are higher at 2 hr after injection of 10-15 mg/kg of morphine (Barjavel et al, 1995;Shang et al, 2006) than they are at 4 hr post-injection, yet the anxiolytic-like effects observed after acute administration of 10 mg/kg morphine peaked at 4 hr, and were absent at 2 hr. Second, the lower dose of morphine (5.6 mg/kg) produces anxiolytic-like effects at 2 hr post-treatment where the higher dose of 10 mg/kg is without effect, yet plasma levels of M3G at 2 hr post-injection are significantly higher with 10 mg/kg than 5.6 mg/kg of morphine (Barjavel et al, 1995;Zheng et al, 1998). Finally, we are unaware of any reports in the literature of M3G producing anxiolytic-like effects, but there are a number of reports that central administration of this morphine metabolite elicits an excitatory reaction characterized by explosive motor behavior, touch-evoked agitation, myoclonic jerks, and wetdog shakes, behaviors that the rat is most likely to experience as aversive rather than anxiolytic (Bartlett et al, 1994;Hemstapat et al, 2003;Labella et al, 1979;Smith and Smith, 1998).…”

Dual, Hyperalgesic, and Analgesic Effects of the High-Efficacy 5-Hydroxytryptamine 1A (5-HT1A) Agonist F 13640 [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, Fumaric Acid Salt]: Relationship with 5-HT1A Receptor Occupancy and Kinetic Parameters

“…Very few data are available in the literature concerning the measurement of drug concentrations in the brain, using microdialysis, after systemic administration. Estimations of morphine concentrations measured in microdialysis samples have been reported previously (Barjavel et al, 1995). In this case, the concentrations of morphine were measured by radioimmunoassay.…”