title: Spinal L-type calcium channel blockade abolishes opioid-induced sensory hypersensitivity and antinociceptive tolerance.
abstract: Recent studies have suggested that prolonged exposure to morphine results in the development of paradoxical, abnormal enhanced pain. It has also been suggested that this enhanced pain state may be interpreted as antinociceptive tolerance. Although the precise mechanisms that drive opioid-induced abnormal pain are not well known, considerable evidence suggests that this state may be supported by enhanced, stimulus-evoked excitatory transmission. We hypothesized that blockade of L-type calcium channels, which are critical for excitatory neurotransmitter release, would alter the development of opioid-induced hyperalgesia and antinociceptive tolerance. Male, Swiss-Webster mice received twice-daily intrathecal injections of morphine (10 microg) alone or in combination with amlodipine (10 microg) for 8 days. Mice receiving repeated morphine injections developed enhanced responses to tactile and thermal stimuli. These hypersensitivities were prevented by the coadministration of the putative selective L-type calcium channel blocker amlodipine. Moreover, mice receiving morphine for 8 days demonstrated a significant rightward shift of the morphine antinociceptive dose-response curve, indicative of antinociceptive tolerance, whereas those that also received amlodipine along with morphine did not demonstrate tolerance. These results suggest that blockade of the L-type calcium channels with amlodipine prevented opioid-induced hyperalgesia and the expression of antinociceptive tolerance to spinal morphine, presumably by reducing stimulus-induced excitatory neurotransmitter release.
authors.affiliation: *Department of Pharmacology, Faculty of Medicine, Gulhane Military Academy of Medicine, Ankara, Turkey; †Department of Pharmacology, University of New England College of Osteopathic Medicine, Biddeford, Maine; and ‡Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogrul
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D004361:Drug Tolerance; D006930:Hyperalgesia / Q000517:prevention & control*; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017311:Amlodipine; D009020:Morphine