I-042 Divakar Budda

A comprehensive binding kinetic model for morphine in the pain matrix regions: what are the most important physiological factors for morphine µ-OR occupancy?

Divakar Budda1, JG Coen van Hasselt1, Elizabeth CM de Lange1

(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.

Introduction:

Morphine remains the primary treatment option for chronic pain. Morphine acts by binding to the µ-opioid receptor (µ-OR) in several CNS regions, including periaqueductal grey, amygdala, hypothalamus, rostral anterior cingulate cortex, rostroventromedial medulla, and medullary dorsal horns, referred together as “Pain matrix”[1-3]. Morphine is primarily metabolized into morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G). While morphine and M6G have analgesic properties, M3G has pro-nociceptive effects counteracting analgesia[4-5]. To bind to the µ-OR in the CNS, morphine and its metabolites have to cross the blood-brain barrier (BBB).  Morphine’s BBB transport involves a saturable influx transporter, leading to nonlinear CNS exposure[6], indicating that  receptor occupancy (RO) profiles for morphine and its metabolites may not be linear with dose. Importantly, age, sex, and chronic morphine dosing, may be associated with differences in CNS drug disposition as well as CNS-region specific µ-OR receptor expression. Moreover, competition with endogenous opioids for binding to the µ-OR receptor may further impact differences in RO[7]. To this end, an integrated quantitative evaluation of CNS exposure and receptor binding kinetics of morphine and its metabolites is essential to design optimal dosing strategies.

Objectives: To evaluate the impact of 1. nonlinear CNS exposure of morphine; 2. age, sex, and chronic morphine dose, and 3. endogenous competition on µ-OR occupancy profiles of morphine and its metabolites, for different clinical dosing strategies.

Methods:

We predicted morphine unbound concentrations in the brain extracellular fluid (brainECF) and cerebrospinal fluid in the subarachnoid space (CSFSAS), using the validated rat and human CNS physiologically based (PBPK) model (LeiCNS PK3.0) including morphine’s nonlinear BBB transport[6], at steady-state conditions after 7 days repeated morphine clinically relevant dosing (20-120mg). The resulting concentrations were taken as input for prediction of morphine, M3G and M6G µ-OR occupancies in the different binding kinetic models with morphine metabolite competition, context dependencies, and competition with endogenous opioids. For simulation of µ-OR occupancies in the pain matrix representative regions, binding kinetic rate constants were calculated based on the diffusion limited binding principle[8].

For context dependent µ-OR expression, µ-OR expression differences for young (<6 months) versus old (>12-24 months), male versus female, and healthy versus chronic pain rats were extracted from literature for pain matrix regions. For human, µ-OR expressions were calculated using the human protein atlas mRNA OPRM1[9].

For µ-OR occupancy competition between morphine and endogenous opioids, literature data for met-enkephalin, leu-enkephalin, beta-endorphin, dynorphinA1.17 and endomorphin 2 concentrations in hypothalamus of rat were used. Moreover, µ-OR turnover and ligand-receptor complex internalizations were examined for their effect on morphine’s µ-OR occupancy.

All simulations were performed using R.

Results:

Pain matrix µ-OR occupancies:

Following oral dosing between 0.25 and 50mg, the ratio of  µ-OR occupancies for morphine: M6G: M3G were 48%: 29%: 23% for brainECF supplied midbrain region, and 76%: 12%: 12% for CSFSAS supplied spinal cord region. For higher (>50mg) oral doses the ratio was 27%: 50%: 23% for midbrain, and 55%: 25%: 20% for spinal cord for morphine: M6G: M3G respectively.

Context dependent µ-OR expression:  Only for ageing a consistent decline in µ-OR expression has been reported, while for sex and chronic morphine conditions no clear differences have been found. The changes in µ-OR expression related to age did however not result in any differences in µ-OR occupancy profile of morphine.

Conclusion: Morphine’s µ-OR occupancy is affected by morphine’s nonlinear BBB transport and competition of µ-OR binding by M3G, M6G and endogenous ligands. In contrast, differences in µ-OR expression related to age, sex and pain conditions do not significantly affect µ-OR occupancy of morphine.

References:

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  6. Gülave B et al Eur J Pharm Sci 2023. https://doi.org/10.1016/J.EJPS.2023.106482
  7. De Witte WEA et al., Br J Pharmacol 2018. https://doi.org/10.1016/j.ejps.2017.05.024
  8. Cruickshank C., Proceedings of Royal Society of London 1924. https://doi.org/10.1098/RSPA.1924.0100
  9. Sjöstedt, E., et al Science 2020. https://doi.org/10.1126/SCIENCE.AAY4106

Reference: PAGE 32 (2024) Abstr 11228 [www.page-meeting.org/?abstract=11228]

Poster: Drug/Disease Modelling - Other Topics