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Pharmacological profile of intrathecal fadolmidine, a α2-adrenoceptor agonist, in rodent models

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Abstract

The present experiments compared the peripheral and central pharmacological effects of three α2-adrenoceptor agonists: fadolmidine, clonidine, and dexmedetomidine after single intrathecal bolus injections at analgesic dose level in rats. Effects on mydriasis and cardiovascular functions were studied in anaesthetised rats, the effects on sedation/motor performance, body temperature, and gastrointestinal motility were evaluated in conscious rats, and also the effects on brain biogenic amines were studied. All compounds caused dose-dependent mydriasis, a decrease in blood pressure and heart rate, sedation, hypothermia, and inhibition of gastrointestinal transit, but in contrast to the analgesic effects, dexmedetomidine and clonidine were much more potent than fadolmidine. In accordance with the other systemic effects, dexmedetomidine and clonidine, but not fadolmidine, reduced the turnover of the monoamine neurotransmitters, noradrenaline and serotonin, in brain at the analgesic dose. The difference in the systemic effect profile between fadolmidine and clonidine or dexmedetomidine is most probably explained by differences in their ability to spread from the site of administration at the lumbar level into the periphery and/or the brain and further the concentrations of the compounds in the side of action. These results supports that intrathecally administered fadolmidine could have potential to be used as an analgesic agent with less subraspinal or spinal adverse effects at analgesic doses than dexmedetomidine and clonidine.

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Acknowledgements

We would like to thank Dr. Jarmo S. Salonen for providing us information about the preliminary rat distribution study results, noted in discussion. We would also like to thank Ms. A. Alatupa, Ms. M. Hassinen, Ms. M. Ojala, and Ms. P. Saikkonen for their experienced technical assistance.

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Authors and Affiliations

  1. Orion Corporation, Orion Pharma, R&D, P.O. Box 425, 20101, Turku, Finland

    Tiina Leino, Timo Viitamaa, Antti Haapalinna, Jyrki Lehtimäki & Raimo Virtanen

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  1. Tiina Leino
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  2. Timo Viitamaa
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  3. Antti Haapalinna
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  4. Jyrki Lehtimäki
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  5. Raimo Virtanen
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Correspondence to Tiina Leino.

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Leino, T., Viitamaa, T., Haapalinna, A. et al. Pharmacological profile of intrathecal fadolmidine, a α2-adrenoceptor agonist, in rodent models. Naunyn-Schmied Arch Pharmacol 380, 539–550 (2009). https://doi.org/10.1007/s00210-009-0460-6

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  • DOI: https://doi.org/10.1007/s00210-009-0460-6

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