Morphine-3-glucuronide: evidence to support its putative role in the development of tolerance to the antinociceptive effects of morphine in the rat

Abstract

Antinociceptive tolerance to morphine (MOR) was induced in groups of Sprague-Dawley rats receiving continuous intravenous infusions of morphine sulphate administered by 3 different MOR dosing regimes. At appropriate intervals throughout each infusion period, antinociceptive testing was performed using the tail-flick latency test and blood samples were collected. Groups of saline (SAL)-infused control rats also underwent antinociceptive testing and blood sample collection. Complete antinociceptive tolerance developed during each MOR infusion period and was characterized by a marked decline in the degree of antinociception from values greater than 90% of the maximum possible effect (%MPE) to pre-dosing baseline values. By contrast, %MPE values in SAL-infused control animals and in sham-operated rats were not significantly different from pre-dosing values throughout the infusion period, indicating that the experimental procedures themselves did not contribute to the development of antinociceptive tolerance to MOR. In addition, the rate of MOR tolerance development was inversely proportional to the MOR infusion rate. A very significant inverse relationship was observed between the mean degree of antinociception (%MPE) and the mean plasma molar concentration ratio, [morphine-3-glucuronide]/[MOR], for each of the 3 MOR dosing regimes and for the cumulated data. This relationship showed that near-maximum antinociception was attainable at ratio values less than approximately 0.50, whilst at ratio values above approximately 1.5, little or no antinociception was observed. Although %MPE was highly inversely correlated with the mean plasma morphine-3-glucuronide (M3G) concentrations for rats receiving regimes A and B, this was not the 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 conclude from this study in Sprague-Dawley rats that irrespective of the rate of antinociceptive tolerance development, the level of antinociception achievable appears to be highly inversely correlated with the mean [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 important determinant. Further research is required in carefully conducted studies in cancer patients to evaluate the possible contribution of the MOR metabolites, M3G and morphine-6-glucuronide (MbG), to increasing dosing requirements of MOR.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship between plasma concentrations of morphine and its metabolites and pain in cancer patients

“…These results were in accordance with those reported by Smith and Smith [30] who found that antinociceptive tolerance to MOR was induced in groups of Sprague-Dawley rats receiving continuous intravenous infusion of MOR, and it was related to the plasma concentration ratio of M3G and MOR. Also, in this study in the comparison of plasma concentrations in patients with VAS pain scores of adequate (VAS B 15 mm) or inadequate (VAS [ 15 mm) pain relief, a simple relationship between plasma concentrations of M3G, M3G/MOR and clinical effect was identified and this correlation was highly significant with M3G/MOR.…”

Impact of sex on pain and opioid analgesia: a review

“…M3G binds to microglial TLR4 to produce hyperalgesia and allodynia (pain response from non-noxious stimuli) (Due et al, 2012), whereas M6G binds to MOR to produce potent pain inhibition (Wittwer and Kern, 2006; see Figure 3). Pharmacological studies show that administration of M3G correlates with nociception (Smith and Smith, 1995) and that M3G actively opposes opioid analgesia, as well as the analgesic effects of M6G (Ekblom et al., 1993; Roeckel et al, 2017;Doyle and Murphy, 2018). …”

Opioid Tolerance Development: A Pharmacokinetic/Pharmacodynamic Perspective

“…In this scenario, time-dependent M3G accumulation could be responsible for the appearance of morphine tolerance. For example, Smith and Smith (22) observed an inverse relationship between morphine-associated antinociception and M3G concentrations. However, careful examination of the influence of M3G pretreatment on morphine antinociception in rats revealed that acute M3G exposure, at concentrations similar to those produced by pharmacologically-relevant doses of morphine, does not attenuate antinociception to a significant extent (23,24).…”