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Efficacy of systemic HS-198, an analogue of oxymorphone, on cancer pain-related behaviour in mice
BMC Pharmacology volume 11, Article number: A4 (2011)
Background
Cancer pain is a significant clinical problem being one of the first symptoms of disease with 75–90% of the patients experiencing chronic pain syndromes in advanced stages [1]. The management of cancer pain is mainly based on the use of opioid drugs; however their clinical use is limited by high incidence of adverse effects. There is a continued search for highly efficacious opioid analgesics with reduced complications and improved patient compliance. An analogue of the clinically used oxymorphone, 5-methyl-substituted 14-O-methyloxymorphone (HS-198), is a selective μ opioid agonist and a potent antinociceptive agent in animal models of nociceptive and inflammatory pain, while exhibiting a favourable dissociation between analgesia and the occurrence of side effects [2]. We report data on efficacy of this opioid agonist after subcutaneous administration (s.c.) in a murine model of cancer pain. The opioid receptor-mechanistic basis of the antinociceptive action was also investigated.
Methods
Cancer pain was induced in C57BL/6J mice by s.c. implantation of lung carcinoma cells, in the plantar and dorsal side of the right hindpaw [3]. Mechanical sensitivity was determined using von Frey monofilaments. Heat sensitivity was assessed using the Hargreaves test. In vitro biological activities were evaluated using binding and functional assays.
Results
On day 9 post-inoculation, s.c. HS-198 produced a dose-dependent inhibition with significant effects in attenuating cancer pain-related behaviour (thermal and mechanical hypersensitivity) on the tumour side. Pre-treatment with the opioid receptor antagonist naloxone reversed the antinociceptive effects induced by HS-198 in mice with cancer-induced pain. In vitro, HS-198 showed high affinity and selectivity for both mouse and rat μ opioid receptors, and it displayed potent μ-agonism through inhibition of G proteins.
Conclusions
Systemic s.c. administration of the μ opioid receptor agonist HS-198 induces potent antinociceptive effects in mice with cancer pain via opioid receptor-specific mechanisms.
References
Mantyh PW: Cancer pain and its impact on diagnosis, survival and quality of life. Nat Rev Biosci. 2006, 7: 797-809.
Schmidhammer H, Spetea M: Synthesis of 14-alkoxymorphinan derivatives and their pharmacological actions. Top Curr Chem. 2011, 299: 63-91.
Constantin CE, Mair N, Sailer CA, Andratsch M, Xu ZZ, Blumer MJ, Scherbakov N, Davis JB, Bluethmann H, Ji RR, Kress M: Endogenous tumor necrosis factor α (TNFα) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model. J Neurosci. 2008, 28: 5072-5081. 10.1523/JNEUROSCI.4476-07.2008.
Acknowledgements
Supported by the Austrian Science Fund (FWF: TRP 19-B18).
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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Asim, M.F., Bohotin, C.R., Constantin, C.E. et al. Efficacy of systemic HS-198, an analogue of oxymorphone, on cancer pain-related behaviour in mice. BMC Pharmacol 11 (Suppl 2), A4 (2011). https://doi.org/10.1186/1471-2210-11-S2-A4
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DOI: https://doi.org/10.1186/1471-2210-11-S2-A4
Keywords
- Naloxone
- Opioid Receptor
- Cancer Pain
- Antinociceptive Effect
- Opioid Agonist