Production of paradoxical sensory hypersensitivity by α 2-adrenoreceptor agonists

Aline Quartilho, Heriberto P. Mata, Mohab M. Ibrahim, Todd W Vanderah, Michael H. Ossipov, Josephine Lai, Frank Porreca, T. Philip Malan

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: Administration of opioid receptor agonists is followed by paradoxical sensory hypersensitivity. This hypersensitivity has been suggested to contribute to the antinociceptive tolerance observed with opioids. The authors hypothesized that α2-adrenoreceptor agonists, which also produce antinociceptive tolerance, would produce sensory hypersensitivity. Methods: α2-Adrenoreceptor agonists were administered to male Sprague-Dawley rats as a single subcutaneous injection, a continuous subcutaneous infusion, a single intrathecal injection, or a continuous intrathecal infusion. Thermal sensitivity was determined using latency to withdrawal of the hind paw from radiant heat. Tactile sensitivity was determined using withdrawal threshold to von Frey filaments. Spinal dynorphin content was measured by enzyme immunoassay. Results: Single systemic or intrathecal injections of clonidine or dexmedetomidine produced antinociception followed by delayed thermal and tactile hypersensitivity. Six-day systemic or intrathecal infusion of clonidine produced tactile and thermal hypersensitivity observed even during clonidine infusion. Sensory hypersensitivity was prevented by coadministration of the α2-adrenoreceptor-selective antagonist idazoxan or the N-methyl-D-aspartate receptor-selective antagonist MK-801. Six-day infusion of intrathecal clonidine increased dynorphin content in dorsal lumbar spinal cord. MK-801 and dynorphin antiserum reversed clonidine-induced sensory hypersensitivity. Conclusions: α 2-Adrenoreceptor agonists produce sensory hypersensitivity that may be analogous to that produced by opioids. Sensory hypersensitivity was prevented by idazoxan, demonstrating that it is mediated by α2 receptors. Clonidine infusion increased spinal dynorphin content. Sensory hypersensitivity was prevented or reversed by MK-801 and dynorphin antiserum, implicating N-methyl-D-aspartate receptors and spinal dynorphin in its production. Clinicians should be mindful of the possibility of drug-induced hyperalgesia in patients treated with α2-adrenoreceptor agonists.

Original languageEnglish (US)
Pages (from-to)1538-1544
Number of pages7
JournalAnesthesiology
Volume100
Issue number6
DOIs
StatePublished - Jun 2004

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Hypersensitivity
Dynorphins
Clonidine
Dizocilpine Maleate
Touch
Hot Temperature
Idazoxan
Spinal Injections
N-Methyl-D-Aspartate Receptors
Opioid Analgesics
Spinal Infusions
Immune Sera
Spinal Cord
Dexmedetomidine
Subcutaneous Infusions
Hyperalgesia
Opioid Receptors
Subcutaneous Injections
Immunoenzyme Techniques
Sprague Dawley Rats

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Quartilho, A., Mata, H. P., Ibrahim, M. M., Vanderah, T. W., Ossipov, M. H., Lai, J., ... Malan, T. P. (2004). Production of paradoxical sensory hypersensitivity by α 2-adrenoreceptor agonists. Anesthesiology, 100(6), 1538-1544. https://doi.org/10.1097/00000542-200406000-00029

Production of paradoxical sensory hypersensitivity by α 2-adrenoreceptor agonists. / Quartilho, Aline; Mata, Heriberto P.; Ibrahim, Mohab M.; Vanderah, Todd W; Ossipov, Michael H.; Lai, Josephine; Porreca, Frank; Malan, T. Philip.

In: Anesthesiology, Vol. 100, No. 6, 06.2004, p. 1538-1544.

Research output: Contribution to journalArticle

Quartilho, Aline ; Mata, Heriberto P. ; Ibrahim, Mohab M. ; Vanderah, Todd W ; Ossipov, Michael H. ; Lai, Josephine ; Porreca, Frank ; Malan, T. Philip. / Production of paradoxical sensory hypersensitivity by α 2-adrenoreceptor agonists. In: Anesthesiology. 2004 ; Vol. 100, No. 6. pp. 1538-1544.
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