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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain
Wataru Ochiai1, Mitsumasa Kaneta1, Marina Nagae1
1Department of Clinical Pharmacokinetics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Abstract:
The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain.
Insights
Chronic morphine use for neuropathic pain leads to tolerance. This study found reduced brain morphine levels in mice with neuropathic pain, correlating with decreased pain relief.
Area of Science:
- Pharmacology
- Neuroscience
- Pain Management
Background:
- Chronic morphine administration can lead to tolerance in neuropathic pain patients.
- Reduced μ-opioid receptor function, particularly with morphine-6-glucuronide (M-6-G), in the midbrain is implicated.
- Mechanisms underlying morphine tolerance in neuropathic pain require further elucidation.
Purpose of the Study:
- To investigate the relationship between brain morphine concentration and analgesic effect in neuropathic pain.
- To examine the expression of key enzymes and transporters involved in morphine metabolism and excretion.
- To understand the impact of neuropathic pain on morphine's pharmacokinetic and pharmacodynamic profile.
Main Methods:
- Oral administration of morphine to mice models of neuropathic pain.
- Analysis of morphine concentration in the brain.
- Measurement of UGT2B (uridine diphosphate glucuronosyltransferase) and P-gp expression levels.
- Correlation analysis between drug concentration, analgesic effect, and enzyme/transporter expression.
Main Results:
- Mice with neuropathic pain exhibited significantly decreased brain morphine concentrations.
- A direct correlation was observed between reduced brain morphine levels and diminished analgesic effects.
- Increased expression of P-gp in the small intestine and UGT2B in the liver was noted.
- Elevated UGT2B expression and binding activity in the liver were also observed.
Conclusions:
- Neuropathic pain may alter morphine pharmacokinetics, leading to reduced central nervous system exposure.
- Increased P-gp and UGT2B activity may contribute to decreased brain morphine and M-6-G levels.
- This reduction in central morphine and M-6-G may explain insufficient analgesia in neuropathic pain patients.
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