Genetic variability in morphine sensitivity and tolerance between different strains of rats.

The development of tolerance, the sensitivity to morphine and the effective morphine plasma concentrations have been studied in Sprague-Dawley (SD-U) and Wistar (W) rats. Daily administration of morphine (10 mg/kg/12 h for 9 days) in W rats produced a reduction in morphine antinociception from day 1 (12+/-0 s) to day 9 (6.7+/-1. 9 s). Morphine antinociception in the SD-U rats did not change over the period of treatment. Naloxone abolished the antinociception of morphine in both opiate naive and chronically treated SD-U rats. The pharmacokinetic parameters of morphine and morphine-3-glucuronide did not differ significantly between strains. Both naive and chronically treated SD-U rats required smaller doses of morphine than W rats to obtain a maximum antinociceptive effect. Plasma concentrations following administration of the same dose of morphine, did not differ between strains or days of treatment. The range of morphine concentrations required to obtain a maximum effect were lower in SD-U rats, both on day 1 and day 8 when compared to W rats. These results show differences between the two strains with regard to both morphine sensitivity and development of tolerance, whilst also suggesting that the differences do not have a kinetic basis.

Morphine-3-glucuronide prevents tolerance to morphine-6-glucuronide in mice.

Daily subcutaneous (s.c.) pretreatment with morphine-3-glucuronide (6 mg/kg) was found to reduce morphine-6-glucuronide (4 mg/kg s.c.)-induced antinociception, with no decrease in the effect over 5 days. Morphine-6-glucuronide administration (4 mg/kg s.c.) on Day 6, without morphine-3-glucorinide pretreatment, results in a significant increase in antinociception (from 24% on Day 5 to 70%; p< or =0.05). Morphine-3-glucuronide may prevent tolerance to morphine-6-glucuronide by reducing morphine-6-glucuronide-induced antinociception.

Cerebrospinal fluid leucine-enkephalin-like levels in febrile convulsions.

Enkephalin levels were measured in the cerebrospinal fluid (CSF) of 17 patients with febrile convulsions and 11 control patients without a history of pain or convulsive disorders. Enkephalins were extracted from CSF by adsorption with synthetic resin XAD-2 eluted with methanol, and assayed using the radioreceptor assay (RRA). Results were expressed as Leucine-Enkephalin (Leu-E) equivalents. Enkephalin levels in CSF were 2.27 +/- 0.42 pmol/ml (mean +/- SE) in the convulsion group and the 4.8 +/- 0.8 pmol/ml (mean +/- SE) in the control group. Statistical comparison in both groups shows significant differences (p less than 0.001). These results suggest a correlation between convulsions and enkephalin levels in CSF.

[Measurement of endorphins in human cerebrospinal fluid. Comparative study of various groups of patients]. / Determinación de endorfinas en LCR humano. Estudio comparativo en distintos grupos de pacientes.

Endorphin levels in human cerebrospinal fluid (CSF) have been determined by using the electrically stimulated mouse vas deferens bioassay. Endorphins were extracted by adsorption to a synthetic resin of Amberlite XAD-2 eluted with methanol, and dried under a nitrogen atmosphere. Three different groups of patients have been studied: a) control subjects without a history of pain (n = 25), b) patients with acute postoperative pain after high abdominal and thoracic surgery (n = 8) and c) patients with chronic pain due to discal hernia (n = 14). The endorphin levels (expressed as equivalents of Met-E) obtained from the control group were 4.36 +/- 0.7 pmol/ml. In the postoperative group an endorphin decrease of 0.42 +/- 0.07 pmol/ml, was found while in the chronic pain group the levels obtained were 1.39 +/- 0.2 pml/ml. Thus a significantly low level of CSF endorphins was observed in both the postoperative and the chronic pain group as compared with the controls (p less than 0.01). These results suggest a correlation between pain levels and endorphin concentration in CSF. However in the acute postoperative pain group other factors such as depletion of endorphins by drugs used for anesthesia or due to surgical stress cannot be excluded.

Endorphin levels in cerebrospinal fluid of patients with postoperative and chronic pain.

The authors measured endorphin levels in the cerebrospinal fluid (CSF) of 12 patients with chronic pain due to lumbar disc syndrome and eight patients with acute postoperative pain. These were compared with CSF endorphin levels in 20 control patients with no history of pain. Endorphins were extracted by adsorption to a synthetic resin (Amberlite XAD-2), eluted with methanol, and assayed using the electrically stimulated mouse vas deferens. Results were expressed as methionine-enkephalin (Met-E) equivalents, which was the standard in the bioassay. The CSF endorphin level was 0.42 +/- 0.07 pmol/ml (mean +/- SE) in the postoperative group, 1.44 +/- 0.2 pmol/ml in the chronic pain group, and 4.36 +/- 0.89 pmol/ml in the control group. CSF endorphin levels in the two pain groups differed significantly from both the control group and each other. These results suggest a correlation between pain levels and endorphin concentration in the CSF; however, in the acute postoperative pain group the influence of other factors such as anesthesia or surgical stress cannot be evaluated.