Pregabalin suppresses spinal neuronal hyperexcitability and visceral hypersensitivity in the absence of peripheral pathophysiology

Kirsty Bannister, Shafaq Sikandar, Claudia S. Bauer, Annette C. Dolphin, Frank Porreca, Anthony H. Dickenson

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Background: Opioid-induced hyperalgesia is recognized in the laboratory and the clinic, generating central hyperexcitability in the absence of peripheral pathology. We investigated pregabalin, indicated for neuropathic pain, and ondansetron, a drug that disrupts descending serotonergic processing in the central nervous system, on spinal neuronal hyperexcitability and visceral hypersensitivity in a rat model of opioid-induced hyperalgesia. Methods: Male Sprague-Dawley rats (180-200 g) were implanted with osmotic mini-pumps filled with morphine (90 μg • μl • h) or saline (0.9% w/v). On days 7-10 in isoflurane anesthetized animals, we evaluated the effects of (1) systemic pregabalin on spinal neuronal and visceromotor responses, and (2) spinal ondansetron on dorsal horn neuronal response. Messenger ribonucleic acid concentrations of α2δ-1, 5HT3A, and μ-opioid receptor in the dorsal root ganglia of all animals were analyzed. Results: In morphine-treated animals, evoked spinal neuronal responses were enhanced to a subset of thermal and mechanical stimuli. This activity was attenuated by pregabalin (by at least 71%) and ondansetron (37%); the visceromotor response to a subset of colorectal distension pressures was attenuated by pregabalin (52.8%; n = 8 for all measures, P < 0.05). Messenger ribonucleic acid concentrations were unchanged. Conclusions: The inhibitory action of pregabalin in opioid-induced hyperalgesia animals is neither neuropathy-dependent nor reliant on up-regulation of the α2δ-1 subunit of voltage-gated calcium channels-mechanisms proposed as being essential for pregabalin's efficacy in neuropathy. In opioid-induced hyperalgesia, which extends to colonic distension, a serotonergic facilitatory system may be up-regulated, creating an environment that is permissive for pregabalin-mediated analgesia without peripheral pathology.

Original languageEnglish (US)
Pages (from-to)144-152
Number of pages9
JournalAnesthesiology
Volume115
Issue number1
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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