title: Pronociceptive and Antinociceptive Effects of Buprenorphine in the Spinal Cord Dorsal Horn Cover a Dose Range of Four Orders of Magnitude.
abstract: Due to its distinct pharmacological profile and lower incidence of adverse events compared with other opioids, buprenorphine is considered a safe option for pain and substitution therapy. However, despite its wide clinical use, little is known about the synaptic effects of buprenorphine in nociceptive pathways. Here, we demonstrate dose-dependent, bimodal effects of buprenorphine on transmission at C-fiber synapses in rat spinal cord dorsal horn in vivo. At an analgesically active dose of 1500 μg·kg(-1), buprenorphine reduced the strength of spinal C-fiber synapses. This depression required activation of spinal opioid receptors, putatively μ1-opioid receptors, as indicated by its sensitivity to spinal naloxone and to the selective μ1-opioid receptor antagonist naloxonazine. In contrast, a 15,000-fold lower dose of buprenorphine (0.1 μg·kg(-1)), which caused thermal and mechanical hyperalgesia in behaving animals, induced an enhancement of transmission at spinal C-fiber synapses. The ultra-low-dose buprenorphine-induced synaptic facilitation was mediated by supraspinal naloxonazine-insensitive, but CTOP-sensitive μ-opioid receptors, descending serotonergic pathways, and activation of spinal glial cells. Selective inhibition of spinal 5-hydroxytryptamine-2 receptors (5-HT2Rs), putatively located on spinal astrocytes, abolished both the induction of synaptic facilitation and the hyperalgesia elicited by ultra-low-dose buprenorphine. Our study revealed that buprenorphine mediates its modulatory effects on transmission at spinal C-fiber synapses by dose dependently acting on distinct μ-opioid receptor subtypes located at different levels of the neuraxis.
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Gerhold
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Ruth
authors.identifier: http://orcid.org/0000-0003-0645-986X
authors.initials: R
authors.lastname: Drdla-Schutting
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Silke D
authors.initials: SD
authors.lastname: Honsek
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Forsthuber
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria juergen.sandkuehler@meduniwien.ac.at.
authors.forename: Jürgen
authors.identifier: http://orcid.org/0000-0002-5209-485X
authors.initials: J
authors.lastname: Sandkühler
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D002047:Buprenorphine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology; D013126:Spinal Nerve Roots / Q000166:cytology; D013569:Synapses / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D009270:Naloxone; D002047:Buprenorphine; C034643:naloxonazine; D010751:Phosphopyruvate Hydratase
keywords: buprenorphine; descending facilitation; opioid; pain; spinal cord; synapse