Development of a canine nociceptive thermal escape model

Abstract

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.

Feasibility and repeatability of cold and mechanical quantitative sensory testing in normal dogs

“…Similar findings were reported in a human study, where cold pain thresholds using a gradually decreasing probe temperature were not obtained before the safety cut-off temperature of 5 °C (Wylde et al, 2011b). It is possible that better results may be obtained by applying a negatively ramped temperature, paralleling ramped hot thermal stimuli (Wegner et al, 2008). Cold thermal testing was successfully employed by Brydges et al (2012) in dogs standing on a cold plate and measuring the time they remained on the cold plate vs. a plate at ambient temperature.…”

Feasibility and repeatability of thermal quantitative sensory testing in normal dogs and dogs with hind limb osteoarthritis-associated pain

“…Wegner et al (2008) described a canine nociceptive thermal escape model (Canine Thermal Escape System or CTES). They tested thermal thresholds in laboratory dogs that were trained and acclimated to the device for 2 weeks, and evaluated changes in response to systemically administered analgesics (Wegner et al, 2008).…”

“…They tested thermal thresholds in laboratory dogs that were trained and acclimated to the device for 2 weeks, and evaluated changes in response to systemically administered analgesics (Wegner et al, 2008). The dogs were restrained in a fabric sling over the thermal stimulus (halogen light) and the anterior center of the metatarsal pad was tested.…”

Current and Future Issues in the development of spinal agents for the management of pain

“…Particularly with regard to pharmacokinetic profiles, large animal models such as dogs, sheep, and primates offer similar metabolic functions [458,475]. Experimental threshold models have been described for these species (see, for example, in dog [476][477][478] and in sheep [479,480]. Such models, while useful, may not capture the complexities of the inflammatory/nerve injury pain states.…”