Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice

Abstract

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 sickling, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickling 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 sickling and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickling 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.

Impaired muscle force production and higher fatigability in a mouse model of sickle cell disease

“…The lower maximal force production (-21% for specific maximal tetanic force) reported here in SCD mice is in accordance with previous studies conducted in humans [3; 4] and in mouse models [6; 7; 9]. As compared to our results, all the animal model studies reported a similar reduction in grip test performance [6; 7; 9; 10; 11] (-18 and -28% for overall and forelimb strength, respectively [6]) while studies conducted in humans indicated a reduced maximal voluntary contraction of forearm muscles (-27% [2], -16% [3] and -23% [4]). In addition, regardless of exercise intensity, the presence of HbS was associated with a significantly slower RFD indicating an impaired kinetics of force development in SCD mice.…”

Cognitive and behavior deficits in sickle cell mice are associated with profound neuropathologic changes in hippocampus and cerebellum

“…In rodent chronic pain models, there is a correlation between nociception alterations and emotionality and mood changes(Tajerian et al, 2014; Zhang et al, 2014). We and others have shown that SCD mice have increased sensitization of sensory nerve fibers, altered nocifensive behavior, and hypersensitivity to noxious stimuli(Calhoun et al, 2015; Kenyon et al, 2015; Kohli et al, 2010). Here we showed that, SCD mice also have cognitive and emotionality and mood disturbances.…”

“…Specifically, in inflammatory pain models, distances ran on the voluntary wheel are significantly reduced by hind paw inflammation, a deficit that is dose-dependently reversed by anti-inflammatory and analgesic drugs(Cobos et al, 2012). We and others have shown that humanized SCD mice have decreased grip force, which is believed to reflect muscle hyperalgesia/pain as after administration of opioids, cannabinoid, or α 2 -adrenoreceptor agonists, grip force increases(Calhoun et al, 2015; Kohli et al, 2010). Therefore, it is conceivable that in SCD mice, muscle hyperalgesia also contributes to reduced muscle strength and decreased voluntary wheel running performance.…”

Comparative Analysis of Pain Behaviours in Humanized Mouse Models of Sickle Cell Anemia

“…BERK sickle mice have been most commonly used to examine the characteristics and mechanisms of pain in SCA [ 4 – 9 , 26 , 30 – 33 ]. Use of Townes sickle mice is emerging to examine hyperalgesia [ 34 , 35 ]. A previous study comparing BERK and Townes mice showed sensitization of peripheral sensory nerve fibers varied according to strain, sex, age, and mouse genotype; and was distinct from that observed in pain models of neuropathic and inflammatory pain [ 35 ].…”