Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis

Abstract

Significance Statement Sickle cell disease (SCD) is accompanied by chronic pain that is difficult to treat. There is evidence that increasing levels of endocannabinoids in the periphery can modulate pain by decreasing excitability of nociceptors. Using a humanized mouse model of SCD, we show that blocking hydrolysis of the endocannabinoid anandamide peripherally with URB597 decreased mechanical hyperalgesia in HbSS-BERK mice. In parallel studies conducted in vivo, it was found that cutaneous nociceptors in sickle mice were sensitized as evidenced by increased spontaneous activity and increased responses to mechanical, heat and cold stimuli. Injection of URB597 decreased sensitization of nociceptors. Thus, decreasing the hydrolysis of endocannabinoids in the periphery may be a novel approach to decrease pain in SCD.

Mast cell‐neural interactions contribute to pain and itch

“…Similarly, sickle mice require a significantly high dose of morphine (20 mg/Kg) to treat tonic hyperalgesia . Electrophysiological recordings show peripheral and central sensitization in these sickle mice . The mechanisms of sickle pain are still emerging, but mast cell activation may contribute to this process based on clinical observations and sickle mice.…”

“…119 Electrophysiological recordings show peripheral and central sensitization in these sickle mice. 40,126 The mechanisms of sickle pain are still emerging, but mast cell activation may contribute to this process based on clinical observations and sickle mice. The skin of sickle mice constitutively has a dense population of degranulating mast cells expressing c-kit, FcεR1, and tryptase with significantly higher transcripts of TLR4.…”

Targeting pain at its source in sickle cell disease

“…In addition to central sensitization, we observed sensitization of cutaneous nociceptors in the periphery in sickle BERK mice (79). Electrophysiological recordings of the tibial nerve in vivo in live anesthetized mice demonstrated spontaneous activity in the A␦ and C fiber nociceptors.…”

Mouse Models of Pain in Sickle Cell Disease

“…Moreover, recurrent exposure to hypoxia/reoxygenation further increases sensitivity to noxious stimuli and further decreases grip force, and these changes persist for several days. A humanized mouse model of pain that recapitulates VOC episodes has applications in translational studies for examining the pathobiology of acute pain and drug development (Belcher et al., ; Hillery et al., ; Kenyon et al., ; Kohli et al., ; Solovey et al., ; Uhelski, Gupta, & Simone, ; Vang et al., ; Vincent et al., ).…”