Development of a canine nociceptive thermal escape model.
Acute nociceptive models which have been validated for large animal species are limited, yet nociceptive assessment in non-rodent species is important in analgesic drug development where larger animals may be necessary because of the technical requirements of the study. Here we report development and validation of a canine hind paw thermal escape model and the effect of analgesics on withdrawal latencies. Individual focused projection bulbs were used as left and right voltage-adjusted thermal stimuli placed below a glass plate in a specifically designed canine holding apparatus. After acclimation, dogs were lightly restrained in a fabric sling while standing on the glass plate. The anterior center of the metatarsal pad of the left and right hind paw was positioned on the glass over each light, and duration of stimulation tolerance timed. For every trial, the escape latency from lamp actuation to paw withdrawal was recorded twice for each hind paw. The mean population baseline withdrawal latency of 9.3+/-1.7s (mean+/-S.D., n=12 dogs) was shown to be repeatable between paws, within and between individual animals, and between test days. This latency corresponded to a glass surface temperature of 49.5 degrees C. A cut-off time of 20s (corresponding to a glass surface temperature of 56.5 degrees C) was set to prevent tissue damage. Intravenous administration (mg/kg) of morphine (1.0), hydromorphone (0.2), butorphanol (0.4), fentanyl (0.01), and dexmedetomidine (0.01) significantly (p<0.05) increased withdrawal latency from baseline within 15-30 min of administration while buprenorphine (0.03) produced a delayed, modest but significant latency increase. Rank order of opioid analgesic duration was morphine=hydromorphone>butorphanol>bupenorphine>fentanyl=saline. A dose-effect curve for hydromorphone was generated and corresponded to previously described dose-effect relationships in other species. The non-analgesic tranquilizer acepromazine (0.1mg/kg) produced mild sedation, but no significant increase in latency from that of saline. The model yielded a clear distinction between analgesia and sedation for all agents tested. These studies provide validation of a canine thermal escape model and have demonstrated the efficacy of clinically relevant doses of analgesics in elevating escape latencies. This model will facilitate quantification of the effects of parenterally and neuraxially administered analgesics in dogs.
Anesthesiology Research, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA. kwegner@ucsd.edu <kwegner@ucsd.edu>
Kirsten
K
Wegner
Kjersti A
KA
Horais
Nicolle A
NA
Tozier
Michael L
ML
Rathbun
Yuri
Y
Shtaerman
Tony L
TL
Yaksh
D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000627:therapeutic use; D000818:Animals; D019540:Area Under Curve; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D007839:Functional Laterality; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008682:Metatarsal Bones / Q000187:drug effects / Q000503:physiopathology; D010147:Pain Measurement / Q000295:instrumentation / Q000379:methods*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D011601:Psychophysics; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology*; D015203:Reproducibility of Results; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid