title: Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain.
abstract: Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.
authors.affiliation: Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Due
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yang
authors.affiliation: Department of Cell Biology and Anatomy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Yohance M
authors.initials: YM
authors.lastname: Allette
authors.affiliation: Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Randolph
authors.affiliation: Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Ripsch
authors.affiliation: Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.affiliation: Department of Cell Biology and Anatomy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Erik T
authors.initials: ET
authors.lastname: Dustrude
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States of America; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.affiliation: Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D002220:Carbamazepine / Q000627:therapeutic use*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D009022:Morphine Derivatives / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D051197:Toll-Like Receptor 4; D002220:Carbamazepine; D009020:Morphine; C018108:morphine-3-glucuronide