MORPHINE-3-GLUCURONIDE - EVIDENCE TO SUPPORT ITS PUTATIVE ROLE IN THEDEVELOPMENT OF TOLERANCE TO THE ANTINOCICEPTIVE EFFECTS OF MORPHINE IN THE RAT

Antinociceptive tolerance to morphine (MOR) was induced in groups of S prague-Dawley rats receiving continuous intravenous infusions of morph ine sulphate administered by 3 different MOR dosing regimes. At approp riate intervals throughout each infusion period, antinociceptive testi ng was performed using the tail-flick latency test and blood samples w ere collected. Groups of saline (SAL)-infused control rats also underw ent antinociceptive testing and blood sample collection Complete antin ociceptive tolerance developed during each MOR infusion period and was characterized by a marked decline in the degree of antinociception fr om values greater than 90% of the maximum possible effect (%MPE) to pr e-dosing baseline values, By contrast, %MPE values in SAL-infused cont rol animals and in sham-operated rats were not significantly different from pre-dosing values throughout the infusion period, indicating tha t the experimental procedures themselves did not contribute to the dev elopment of antinociceptive tolerance to MOR. In addition, the rate of MOR tolerance development was inversely proportional to the MOR infus ion rate. A very significant inverse relationship was observed between the mean degree of antinociception (%MPE) and the mean plasma molar c oncentration ratio, [morphine-3-glucuronide]/[MOR], for each of the 3 MOR dosing regimes and for the cumulated data. This relationship showe d that near-maximum antinociception was attainable at ratio values les s than approximately 0.50, whilst at ratio values above approximately 1.5, little or no antinociception was observed. Although %MPE was high ly inversely correlated with the mean plasma morphine-3-glucuronide (M 3G) concentrations for rats receiving regimes A and B, this was not th e case for rats receiving regime C where antinociceptive tolerance was partially reversed by an increase in the morphine infusion rate part- way through the infusion period. In addition, a poor relationship was observed between %MPE and the mean plasma MOR concentration, possibly due to the confounding presence of M3G in all samples. Thus, we may co nclude from this study in Sprague-Dawley rats that irrespective of the rate of antinociceptive tolerance development, the level of antinocic eption achievable appears to be highly inversely correlated with the m ean [M3G]/[MOR] plasma molar concentration ratio and poorly correlated with the plasma MOR concentration, consistent with the notion that it is perhaps the balance between the excitatory effects of M3G and the inhibitory effects of MOR at the functional level which is the importa nt determinant. Further research is required in carefully conducted st udies in cancer patients to evaluate the possible contribution of the MOR metabolites, M3G and morphine-6-glucuronide (MbG), to increasing d osing requirements of MOR. Other factors such as disease progression a nd increasing psychological distress must also be borne in mind, as th ese will have a major influence on increasing dosing requirements of M OR in cancer patients (Portenoy 1994).