Chemokine (c-c motif) receptor 2 mediates mechanical and cold hypersensitivity in sickle cell disease mice

Abstract

Approximately one-third of individuals with sickle cell disease (SCD) develop chronic pain. This debilitating pain is inadequately treated because the underlying mechanisms driving the pain are poorly understood. In addition to persistent pain, patients with SCD are also in a tonically proinflammatory state. Previous studies have revealed that there are elevated plasma levels of many inflammatory mediators including chemokine (c-c motif) ligand 2 (CCL2) in individuals with SCD. Using a transgenic mouse model of SCD, we investigated the contributions of CCL2 signaling to SCD-related pain. Inhibition of chemokine receptor 2 (CCR2), but not CCR4, alleviated the behavioral mechanical and cold hypersensitivity in SCD. Furthermore, acute CCR2 blockade reversed both the behavioral and the in vitro responsiveness of sensory neurons to an agonist of TRPV1, a neuronal ion channel previously implicated in SCD pain. These results provide insight into the immune-mediated regulation of hypersensitivity in SCD and could inform future development of analgesics or therapeutic measures to prevent chronic pain.

Gabapentin alleviates chronic spontaneous pain and acute hypoxia‐related pain in a mouse model of sickle cell disease

“…Townes SS, Berk SS) recapitulate many qualities of SCD patient phenotypes, including sickled red blood cells, haemolytic anaemia, and hepatic, cardiac and pulmonary pathologies (P aszty et al, 1997;Ryan et al, 1997). Like patients with SCD (Brandow et al, 2013;Jacob et al, 2015), both Townes SS and Berk SS mice exhibit chronic mechanical, cold and heat hypersensitivity that is further exacerbated by hypoxia/reperfusion (H/ R; see below) (Kohli et al, 2010;Hillery et al, 2011;Cain et al, 2012;Zappia et al, 2014;Sadler et al, 2018), an experimental method for inducing an acute vaso-occlusive crisis (VOC). As the Townes and Berk line backgrounds are predominantly C57BL/6 and 129, B6;129 mice were used as the control strain for all experiments.…”

“…Cold allodynia is another common complaint of both neuropathic pain patients and patients with SCD (Woolf & Mannion, 1999;Brandow et al, 2013;Zappia et al, 2014;Sadler et al, 2018). Behaviourally, cold sensitivity was assayed by measuring the withdrawal latency to dry ice stimulation of the hindpaw (Fig 1E).…”

End points for sickle cell disease clinical trials: patient-reported outcomes, pain, and the brain

“…Other potential mechanisms that may drive or contribute to acute or chronic pain in SCD have been demonstrated in murine sickle models but remain to be validated in SCD patients. These include neurogenic inflammatory mediators including: CGRP, tachykinin receptor 1, endothelin 1, endothelin type A receptor, and Nav1.8 channels 174 ; chemo chemokine receptor-5 and m opioid receptors 175 ; ion channels including transient receptor potential vanilloid 1 106 ; and chemokine ligand 2 receptors, 176 Ca/calmodulin-dependent protein kinase II, 177 protein kinase Cd, 178 and cannabinoid receptors. 179 None have yet been validated in human studies.…”

Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain

“…von Frey mechanical allodynia testing. Hindpaw sensitivity to punctate mechanical stimulation was assessed via calibrated von Frey filaments (0.20-13.73 mN) and the up-down assessment method as previously described (59,60). The 50% withdrawal threshold was calculated for each paw as previously described (61).…”