Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice.
Patients with sickle cell disease (SCD) can have recurrent episodes of vaso-occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid-responsive mechanisms. Dexmedetomidine, a specific α2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P≤0.006). In sickle, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickle and control mice as it decreased wakefulness scores compared with vehicle (all P<0.001). Interestingly, the effects of dexmedetomidine on hot plate latency and wakefulness scores were different in sickle and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickle compared to control mice. In conclusion, these findings of beneficial effects of dexmedetomidine on the nociception phenotype in SCD mice might support the conduct of studies of dexmedetomidine in SCD patients.
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children׳s National Health System, Children׳s Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Gabriela
G
Calhoun
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children׳s National Health System, Children׳s Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Li
L
Wang
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children׳s National Health System, Children׳s Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Luis E F
LE
Almeida
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children׳s National Health System, Children׳s Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Nicholas
N
Kenyon
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children׳s National Health System, Children׳s Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Nina
N
Afsar
Center for Sickle Cell Disease and Department of Internal Medicine, Howard University, Washington, DC 20001, United States.
Mehdi
M
Nouraie
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children׳s National Health System, Children׳s Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Julia C
JC
Finkel
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children׳s National Health System, Children׳s Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States. Electronic address: zquezado@childrensnational.org.
Zenaide M N
ZM
Quezado
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000755:Anemia, Sickle Cell / Q000150:complications*; D000818:Animals; D020927:Dexmedetomidine / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018737:Hand Strength; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D010146:Pain / Q000150:complications* / Q000188:drug therapy* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects*; D014828:Vocalization, Animal / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects
D058647:Adrenergic alpha-2 Receptor Agonists; D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine
Dexmedetomidine (PubChem CID: 6918081); Hyperalgesia; Muscle pain; Opioid; Pain; Sickle cell; α(2)-agonist