Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Bullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A.

AIM OF THE STUDY:

To assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparison MATERIALS AND METHODS: Spinal nerve ligation-induced neuropathic rats and naïve mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine.

RESULTS:

Single subcutaneous injection of bullatine A or dynorphin A(1-17) did not either alter formalin- and thermally (hot-plate and water immersion tests)-induced acute nociception or potentiate morphine antinociception in naïve mice. In contrast, bullatine A dose-dependently inhibited formalin-induced tonic pain with the efficacy of 54% inhibition and the half-effective dose of 0.9mg/kg. Concurrent bullatine A additively enhanced morphine antinociception. In neuropathic rats, the antinociceptive effects of multiple bidaily intrathecal injections of bullatine A and dynorphin A remained consistent over 13 days, whereas morphine produced progressive and complete tolerance to antinociception, which was completely inhibited by concurrent bullatine A and dynorphin A. A single intrathecal injection of bullatine A and dynorphin A immediately reversed established morphine tolerance in neuropathic rats, although the blockade was a less degree in the thermally induced mouse acute nociceptive tests. The inhibitory effects of bullatine A and dynorphin A on morphine tolerance were immediately and completely attenuated by intrathecal dynorphin A antibody and/or selective κ-opioid receptor antagonist GNTI.

CONCLUSION:

These results suggest that bullatine A produces antinociception without induction of tolerance and inhibits morphine antinociceptive tolerance, and provide pharmacological basis for concurrent bullatine A and morphine treatment for chronic pain and morphine analgesic tolerance.

• Authors: Qian Huang, Ming-Li Sun, Yuan Chen, Xin-Yan Li, Yong-Xiang Wang
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 196 Pg. 151-159 (Jan 20 2017) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 27989510 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Alkaloids
• Analgesics
• Diterpenes
• Drug Combinations
• Receptors, Opioid, kappa
• bullatine A
• Formaldehyde
• Dynorphins
• Morphine

Topics

• Alkaloids (pharmacology, therapeutic use)
• Analgesics (pharmacology, therapeutic use)
• Animals
• Behavior, Animal (drug effects)
• Diterpenes (pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Combinations
• Drug Tolerance
• Dynorphins (pharmacology, therapeutic use)
• Formaldehyde
• Hot Temperature
• Hyperalgesia (drug therapy, metabolism)
• Male
• Mice
• Microglia (drug effects, metabolism)
• Morphine (pharmacology, therapeutic use)
• Pain (drug therapy, metabolism)
• Rats, Wistar
• Receptors, Opioid, kappa (metabolism)
• Spine (drug effects, metabolism)