The importance of genetic background on pain behaviours and pharmacological sensitivity in the rat spared serve injury model of peripheral neuropathic pain.
Neuropathic pain conditions can encompass a diverse constellation of signs and symptoms consisting of sensory deficits, allodynia and hyperalgesia. Animal models of neuropathic pain have enabled the identification of key pathophysiological changes occurring within nociceptive pathways as a result of injury, and serve an invaluable role for preclinical screening of novel analgesic candidates. We have produced the first systematic description of the development and maintenance, and the pharmacological sensitivity of nociceptive behaviours in four rat strains with different genetic background (outbred Sprague-Dawley and inbred Brown Norway, Lewis and Fischer 344 rats), using the spared nerve injury model of peripheral neuropathic pain. Hindpaw mechanical hypersensitivity was evident from 7 to 30 days post-injury in all four strains, developing most quickly and severely in Fischer 344 rats; Lewis rats were least affected. Morphine (6 but not 3 mg/kg, s.c.) and gabapentin (100 but not 50 mg/kg, s.c.) had significant antiallodynic and antihyperalgesic actions in all four strains after spared nerve injury, although marked differences in potency across strains were observed. Two strains (Fischer 344 rats and Lewis) were insensitive to the antihyperalgesic properties of gaboxadol (15 mg/kg) whereas gaboxadol (6 mg/kg) was equipotent to morphine (6 mg/kg) in two other strains (Sprague-Dawley and Brown Norway). The observed pharmacogenetic variations have important implications for the preclinical testing of drugs, and provide a basis for development of pharmacogenomics in neuropathic pain.
Rode
Frederik
F
Department of Pharmacology, Danish University of Pharmaceutical Sciences, Jagtvej 120, Copenhagen, Denmark. Frederikrode@hotmail.com
Thomsen
Mads
M
Broløs
Tine
T
Jensen
Dorthe G
DG
Blackburn-Munro
Gordon
G
Bjerrum
Ole J
OJ
D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D006614:Hindlimb; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy* / Q000235:genetics*; D010147:Pain Measurement / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D059348:Peripheral Nerve Injuries; D010597:Pharmacogenetics; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013045:Species Specificity; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology
D000588:Amines; D000700:Analgesics; D000701:Analgesics, Opioid; D003509:Cyclohexanecarboxylic Acids; D007555:Isoxazoles; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine; C015542:gaboxadol