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Papers of the Week

Papers: 29 Feb 2020 - 6 Mar 2020

Animal Studies, Pharmacology/Drug Development

2020 Feb 26

Eur J Pharmacol

Morphine-3-glucuronide causes antinociceptive cross-tolerance to morphine and increases spinal substance P expression.


Blomqvist KJ, Viisanen H, Ahlström FHG, Jokinen V, Sidorova YA, Suleymanova I, Rauhala PV, Kalso EA, Lilius TO
Eur J Pharmacol. 2020 Feb 26:173021.
PMID: 32112778.


Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.