Dose-Dependent Effects of Icilin on Thermal Preference in the Hindpaw and Face of Rats

Abstract

Icilin induces wet dog shakes (WDS) in rodents when injected systemically and activates the cold receptor TRPM8 and putative cold receptor TRPA1. It is assumed that WDS reflect an enhanced cold sensitivity; however, none have examined the relationship between WDS and cutaneous cold sensitivity following systemic icilin. In this study, we sought to characterize the effect of systemic and central icilin administration on WDS and thermal preference with either hindpaw or facial stimulation. It was found that a low dose of icilin (0.025mg), which transiently elevated WDS, decreased preference for cold with hindpaw stimulation (15 and 45°C) when administered i.p. or i.t. Intracisternal administration of this dose produced similar results for facial stimulation (10 and 48°C), but had no effect when administered i.p. In contrast a high dose of icilin (0.25mg), which persistently elevated WDS, strongly increased preference for cold with hindpaw stimulation and had no effect on thermal preference with facial stimulation. These findings indicate that at the low concentration, systemic and central icilin enhances cold sensitivity, likely via TRPM8 and TRPA1 activation. In contrast, systemic icilin at the high concentration produces peripheral and/or central effects that diminish cold sensitivity, while WDS is maintained at a persistent rate.Perspective-Icilin is a unique compound that produces dissociable effects on an innate behavior (WDS) and on operant behaviors related to thermal perception. This compound could help clarify the relationship between peripheral cold transduction and the central induction of thermogenesis and nocifensive behaviors, as well as alterations that produce pathological pain.

Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat

“…In icilin‐induced WDS, a model of skeletal muscle‐mediated heat generation in which the role of TRPM8 has been widely characterized (Werkheiser et al, ; Rossi et al, ), systemic administration of the drugs was able to reduce the numbers of WDS produced by icilin, in line with previous literature (Tamayo et al, ; Lehto et al, ). Gavva et al .…”

Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons

“…This raises the question of whether intrathecally injected drug can access the DRG cell body. Three-dimensional CT reconstruction in the rat after ICM injection of contrast agent showed enhancement of signal around the cervical spinal cord without enhancement around trigeminal ganglia (64). This same type of limited drug access was evaluated in a single human subject using low-concentration gadolinium dye tracing in the CSF ( Figure 5).…”

TRPM8: From Cold to Cancer, Peppermint to Pain

“…However, dogs, with body temperatures exceeding 38°C, have a version of TRPM8 activated around 17°C, indicating that this generalization may be more nuanced than proposed [85]. Nevertheless, systemic icilin administration induces a dosedependent hyperthermia that is initiated outside of the brain, as well as autonomic and active thermoregulatory behaviors [86,87]. Similarly to cold exposure, either intragastric or topical menthol leads to increased body temperature and thermogenic behaviors [76,88,89].…”