Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury.
Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether (1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and (2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3-4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10mg/kg, subcutaneous, s.c.), followed 30min later by either saline or midazolam (2mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10mg/kg, s.c.), midazolam (2mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor, 10nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism.
MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Anesthesia, West China Hospital, Sichuan University, Chengdu, China.
Li
L
Song
MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Shuxing
S
Wang
Department of Anesthesia, West China Hospital, Sichuan University, Chengdu, China.
Yunxia
Y
Zuo
MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Lucy
L
Chen
MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Jeevendra A
JA
Martyn
MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: jmao@partners.org.
Jianren
J
Mao
D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D002056:Burns / Q000188:drug therapy*; D004361:Drug Tolerance; D006930:Hyperalgesia / Q000188:drug therapy; D006948:Hyperkinesis / Q000139:chemically induced*; D006993:Hypnotics and Sedatives / Q000633:toxicity*; D008297:Male; D008874:Midazolam / Q000633:toxicity*; D009020:Morphine / Q000633:toxicity*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; D011493:Protein Kinase C; D008874:Midazolam
Burn injury; Hyperactivity; Midazolam; Morphine tolerance; NMDA; NR1; PKC; Young rats