Icilin-induced wet-dog shakes in rats are dependent on NMDA receptor activation and nitric oxide production

Department of Pharmacology, Temple University Health Sciences Center, Philadelphia, PA 19140, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 03/2009; 92(3):543-8. DOI: 10.1016/j.pbb.2009.02.005
Source: PubMed


Icilin is a cold channel agonist that produces vigorous wet-dog shaking in rats. The shaking is accompanied by an increase in the level of extracellular glutamate in the brain. Hence, we hypothesized that icilin-induced wet-dog shakes are dependent on increased glutamatergic transmission and nitric oxide (NO) production. Rats injected with icilin (0.5, 1, 2.5, 5 mg/kg, i.p.) displayed a dose-related increase in wet-dog shakes. Pretreatment with LY 235959 (1, 2 mg/kg, i.p.), a NMDA receptor antagonist, or L-NAME (50 mg/kg, i.p.), a NO synthase (NOS) inhibitor, attenuated icilin-induced wet-dog shakes. The shaking was also reduced by intracerebroventricular L-NAME (1 mg/rat, i.c.v.) administration, indicating that the stimulant effect of icilin is dependent on central NO production. Pretreatment with 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) (10, 20 mg/kg, i.p.), an AMPA receptor antagonist, or ceftriaxone (200 mg/kg, i.p. for 5 days), a beta-lactam antibiotic and glutamate transporter subtype 1 (GLT-1) activator, did not alter the incidence of icilin-induced shaking. The present data reveal that icilin produces behavioral stimulation by a mechanism requiring NMDA receptor activation and nitric oxide production and suggest that glutamate and NO signaling play important roles in cold channel pharmacology.

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    • "Furthermore, the glutamatergic projections of VTA into amygdala are graded as main component in the expression of morphine dependence.[23] Our result, thus, in accordance to a previous investigation,[24] may provide a finding that the NO in the CeA plays an important role in expression of withdrawal aspects of morphine conditioning. However, in other set of our experiments, the injection of L-NAME (0.3-3 μg/rat, intra-CeA) prior to L-arginine microinjection (1 μg/rat, intra-CeA) did not block the L-arginine dose effect in comparison to control. "
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    ABSTRACT: The aim of this study was to evaluate if nitric oxide (NO) in the central amygdala (CeA) is involved in the expression of withdrawal aspects induced by morphine. Male Wistar rats (weighing 200-250 g) were bilaterally cannulated in the CeA and conditioned to morphine using an unbiased paradigm. Morphine (2.5-10 mg/kg) was subcutaneously injected once a day throughout the conditioning phase of the procedure. This phase also included 3-saline paired sessions. Naloxone (0.1-0.4 mg/kg, intraperitoneally [i.p.]), an antagonist of opioid receptors, was administered i.p. 10 min prior to testing of morphine-induced withdrawal features. The NO precursor, L-arginine (0.3-3 μg/rat) was intra-CeA injected prior to testing of naloxone response. To evaluate the involvement of NO system an inhibitor of NO synthase (NOS), N(G)-nitro-L-arginine methyl ester (L-NAME) (0.3-3 μg/rat), was injected ahead of L-arginine. Control group received saline solely instead of drug. As a complementary study, the activation of NOS was studied by nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d). Morphine induced a significant increase in wet dog shaking and grooming behaviors compared with controls. Injection of naloxone pre-testing of morphine response significantly reversed the response to morphine. However, pre-microinjection of L-arginine intra-CeA recovered the response to morphine. Injection of L-NAME intra-CeA ahead of L-arginine though had no effect behaviorally, but, inhibited the NOS which has been evidenced by NADPH-d. The present study shows that NO in the CeA potentiates the expression of conditioned withdrawal induced by morphine paired with naloxone.
    Indian Journal of Pharmacology 03/2014; 46(1):57-62. DOI:10.4103/0253-7613.125169 · 0.69 Impact Factor
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    • "Indeed, TRPV1 and TRPA1 have overlapping expression in a subset of DRG neurons (Story et al., 2003) and thereby could potentially interact via intracellular signaling in vivo. Recently, icilin, an agonist of TRPA1 and TRPM8, has been implicated as a trigger for shaking and hyperthermia which require NO production and NMDA receptor activation (Ding et al., 2008; Werkheiser et al., 2009). In this context, it would be interesting to explore the mechanism of the concerted regulation of Ca 2+ and NO signaling by the TRP channels, NMDA receptors and nNOS in neurons. "
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    ABSTRACT: The transient receptor potential (trp) gene superfamily encodes cation channels that act as multimodal sensors for a wide variety of stimuli from outside and inside the cell. Upon sensing, they transduce electrical and Ca(2+) signals via their cation channel activities. These functional features of TRP channels allow the body to react and adapt to different forms of environmental changes. Indeed, members of one class of TRP channels have emerged as sensors of gaseous messenger molecules that control various cellular processes. Nitric oxide (NO), a vasoactive gaseous molecule, regulates TRP channels directly via cysteine (Cys) S-nitrosylation or indirectly via cyclic GMP (cGMP)/protein kinase G (PKG)-dependent phosphorylation. Recent studies have revealed that changes in the availability of molecular oxygen (O(2)) also control the activation of TRP channels. Anoxia induced by O(2)-glucose deprivation and severe hypoxia (1% O(2)) activates TRPM7 and TRPC6, respectively, whereas TRPA1 has recently been identified as a novel sensor of hyperoxia and mild hypoxia (15% O(2)) in vagal and sensory neurons. TRPA1 also detects other gaseous molecules such as hydrogen sulfide (H(2)S) and carbon dioxide (CO(2)). In this review, we focus on how signaling by gaseous molecules is sensed and integrated by TRP channels.
    Frontiers in Physiology 08/2012; 3:324. DOI:10.3389/fphys.2012.00324 · 3.53 Impact Factor
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    • "Our studies have traditionally focused on the identification of downstream signaling events that underlie icilin-induced behavioral activation. For example, we have demonstrated that icilin-induced WDS are dependent on NMDA receptor activation and nitric oxide production but not on AMPA receptor or glutamate transporter subtype 1 (GLT-1) activation (Werkheiser et al., 2009). We have also shown that mu and kappa opioid receptor agonists reduce icilin-induced shaking (Werkheiser et al., 2006). "
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    ABSTRACT: Icilin is a transient receptor potential cation channel subfamily M (TRPM8) agonist that produces behavioral activation in rats and mice. Its hallmark overt pharmacological effect is wet-dog shakes (WDS) in rats. The vigorous shaking associated with icilin is dependent on NMDA receptor activation and nitric oxide production, but little else is known about the biological systems that modulate the behavioral phenomenon. The present study investigated the hypothesis that alpha(2)-adrenoceptor activation inhibits icilin-induced WDS. Rats injected with icilin (0.5, 1, 2.5, 5mg/kg, i.p.) displayed dose-related WDS that were inhibited by pretreatment with a fixed dose of clonidine (0.15 mg/kg, s.c.). Shaking behavior caused by a fixed dose (2.5mg/kg) of icilin was also inhibited in a dose-related manner by clonidine pretreatment (0.03-0.15 mg/kg, s.c.) and reduced by clonidine posttreatment (0.15 mg/kg, s.c.). Pretreatment with a peripherally restricted alpha(2)-adrenoceptor agonist, ST91 (0.075, 0.15 mg/kg), also decreased the incidence of shaking elicited by 2.5mg/kg of icilin. Pretreatment with yohimbine (2mg/kg, i.p.) enhanced the shaking induced by a low dose of icilin (0.5mg/kg). The imidazoline site agonists, agmatine (150mg/kg, i.p.) and 2-BFI (7 mg/kg, i.p.), did not affect icilin-evoked shaking. These results suggest that alpha(2)-adrenoceptor activation inhibits shaking induced by icilin and that increases in peripheral, as well as central, alpha(2)-adrenoceptor signaling oppose the behavioral stimulant effect of icilin.
    Brain research 02/2011; 1384:110-7. DOI:10.1016/j.brainres.2011.02.002 · 2.84 Impact Factor
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