Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

Abstract

Icilin, a cooling compound, produces vigorous wet-dog shakes in rats. We have reported previously that icilin-induced wet-dog shakes are blocked by the kappa opioid receptor agonists, nalfurafine and U50,488H, and that icilin evokes a dose- and time-dependent increase in glutamate within the dorsal striatum. Since activation of kappa opioid receptors inhibits glutamate release intrastriatally, we targeted glutamate release within the dorsal striatum using nalfurafine and examined the role of the dorsal striatum in icilin-induced wet-dog shakes, more specifically, the effect that icilin-evoked intrastriatal glutamate release has on the overt stimulant behavior. We report that nalfurafine (0.04mg/kg) inhibits icilin (0.50mg/kg)-induced wet-dog shakes and that this inhibition is reversed by intrastriatal perfusion of the kappa opioid receptor antagonist, norbinaltorphimine (100nM). Furthermore,we antagonized icilin-evoked glutamate release with nalfurafine (0.04mg/kg), and reversed inhibition of glutamate release with intrastriatal norbinaltorphimine (100nM). These findings support a central component in the behavioral response to icilin and suggest that activation of kappa opioid receptors antagonizes icilin-induced wet-dog shakes in rats by inhibiting glutamate release within the dorsal striatum.

Fig.1

A representative cresyl violet (0.5%) stained brain section that depicts probe placement and histological damage resulting from insertion of microdialysis probe and subsequent microdialysis experiment. The anatomical placement within the dorsal striatum of all dialysis probes used in the study (AP +0.8 mm, ML +3.0 mm DV-4.0 mm) was based on Paxinos and Watson (1997). CC=Corpus callosum; DS= Dorsal striatum.

Fig. 2

A. Rats were injected with either icilin or vehicle after the 0 min collection. At 15 min, 0.50 mg/kg icilin (■) increased glutamate levels significantly compared to icilin rats pretreated with nalfurafine (▲) or controls [saline (sal)/vehicle (veh) (●) or nalfurafine (nalfur)/veh (▼)] as well as pretreatment levels (**p<0.01; two-way ANOVA followed by Bonferroni post hoc test). B. Area under the curve (AUC) was analyzed for the first 60 min (15-60 min) following icilin and confirmed inhibition of icilin-evoked glutamate release by nalfurafine (**p< 0.01; one way ANOVA followed by Newman Keuls post-hoc test). Nalfurafine had no effect on glutamate levels compared to pretreatment glutamate levels or saline/vehicle.

Fig. 3

Perfusion of norbinaltorphimine (NBNI) directly into the dorsal striatum significantly reversed nalfurafine inhibition of icilin (0.5 mg/kg)-induced wet-dog shakes (WDS) over the 30 min test period (* p< 0.05; one-way ANOVA followed by Newman Keuls post-hoc test).

Fig. 4

AUC analysis for the first 60 min following icilin showed that NBNI significantly (** p<0.01) reversed nalfurafine inhibition of icilin (0.05 mg/kg) evoked glutamate increase (one-way ANOVA followed by Newman-Keuls post-hoc test).