title: Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target.
abstract: 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.
authors: Centre for Pain Research, Institute for Molecular Bioscience, University of Queensland, Queensland, Australia.
authors: Kathleen
authors: K
authors: Yin
authors: Centre for Pain Research, Institute for Molecular Bioscience, University of Queensland, Queensland, Australia.
authors: Jennifer R
authors: JR
authors: Deuis
authors: Centre for Pain Research, Institute for Molecular Bioscience, University of Queensland, Queensland, Australia.
authors: Richard J
authors: RJ
authors: Lewis
authors: Centre for Pain Research, Institute for Molecular Bioscience, University of Queensland, Queensland, Australia Pharmacy Australia Centre of Excellence, University of Queensland, Queensland, Australia i.vetter@uq.edu.au.
authors: Irina
authors: I
authors: Vetter
mesh_terms: D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use; D000639:Amitriptyline / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D000077206:Gabapentin; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology*; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology*; D008297:Male; D008663:Metacarpus / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010098:Oxycodone / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D011377:Proglumide / Q000494:pharmacology / Q000627:therapeutic use; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects; D059467:Transcriptome; D016474:Weight-Bearing / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D043887:Receptor, Cholecystokinin B; D000639:Amitriptyline; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D010098:Oxycodone; D011377:Proglumide
keywords: Burn-induced pain; animal models; dorsal root ganglion neurons; proglumide; transcriptome