Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target
Burn injury is a cause of significant mortality and morbidity worldwide and is frequently associated with severe and long lasting pain that remains difficult to manage throughout recovery. We characterised a mouse model of burn induced pain using pharmacological and transcriptomic approaches. Mechanical allodynia elicited by burn injury was partially reversed by meloxicam (5 mg/kg) gabapentin (100 mg/kg) and oxycodone (3 and 10 mg/kg) while thermal allodynia and gait abnormalities were only significantly improved by amitriptyline (3 mg/kg) and oxycodone (10 mg/kg) The need for relatively high opioid doses to elicit analgesia suggested a degree of opioid resistance, similar to that shown clinically in burn patients. We thus assessed the gene expression changes in dorsal root ganglion neurons and pathophysiological mechanisms underpinning burn injury induced pain using a transcriptomic approach. Burn injury was associated with significantly increased expression of genes associated with axon guidance, neuropeptide signalling, behavioural defence response and extracellular signalling, confirming a mixed neuropathic and inflammatory aetiology. Notably, among the pain related genes that were upregulated post injury was the cholecystokinin 2 receptor (Cckbr) a G protein coupled receptor known as a pain target involved in reducing opioid effectiveness. Indeed, the clinically used cholecystokinin receptor antagonist proglumide (30 mg/kg) was effective at reversing mechanical allodynia, with additional analgesia evident in combination with low dose oxycodone (1 mg/kg) including significant reversal of thermal allodynia. These findings highlight the complex pathophysiological mechanisms underpinning burn injury induced pain and suggest that cholecystokinin 2 receptor antagonists may be useful clinically as adjuvants to decrease opioid requirements and improve analgesic management.
Molecular pain