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

Werkheiser, Jennifer L.; Cowan, Alan; Gómez, Teresa; Henry, Craig; Parekh, Shreya; Chau, Sony; Baron, David

doi:10.1016/j.pbb.2009.02.005

Cited by 11 publications

(19 citation statements)

References 51 publications

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“…[22] 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.…”

Section: Discussionsupporting

confidence: 92%

Nitric oxide in central amygdala potentiates expression of conditioned withdrawal induced by morphine

et al. 2014

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Objective: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.Materials and Methods: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), NG-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).Results: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.Conclusion:The present study shows that NO in the CeA potentiates the expression of conditioned withdrawal induced by morphine paired with naloxone.

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Section: Discussionsupporting

confidence: 92%

Nitric oxide in central amygdala potentiates expression of conditioned withdrawal induced by morphine

et al. 2014

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“…These responses were inhibited by DFL23448 by approximately 40%. Because the icilin WDS test reflects somatomotor cold behaviors, we also assessed effects of DFL23448 on visceral in vivo responses to cold (Werkheiser et al, 2009). TRPM8 was recently identified as the main mediator for the skin-cooling bladder reflex in rats and this model is proposed as relevant to simulate human acute cold-induced urgency (Uvin et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

Mistretta

Russo

Castiglione

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The transient receptor potential melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity is available. This study characterizes a new TRPM8-selective antagonist (DFL23448 [5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol]) and evaluates it in cold-induced behavioral tests and tests on bladder function and experimental bladder overactivity in vivo in rats. DFL23448 displayed IC 50 values of 10 and 21 nM in hTRPM8 human embryonic kidney 293 cells activated by Cooling Agent 10 or cold, but it had limited activity (IC 50 . 10 mM) at transient receptor potential vanilloids TRPV1, TRPA1, or TRPV4 or at various G protein-coupled receptors. In rats, DFL23448 administered intravenously or orally had a half-life of 37 minutes or 4.9 hours, respectively. DLF23448 (10 mg/kg i.v.) reduced icilininduced "wet dog-like" shakes in rats. Intravesical DFL23448 (10 mg/l), but not vehicle, increased micturition intervals, micturition volume, and bladder capacity. During bladder overactivity by intravesical prostaglandin E 2 (PGE 2 ), vehicle controls exhibited reductions in micturition intervals, micturition volumes, and bladder capacity by 37%-39%, whereas the same parameters only decreased by 12%-15% (P , 0.05-0.01 versus vehicle) in DFL23448-treated rats. In vehicle-treated rats, but not in DFL23448-treated rats, intravesical PGE 2 increased bladder pressures. Intravenous DFL23448 at 10 mg/kg, but not 1 mg/kg DFL23448 or vehicle, increased micturition intervals, micturition volumes, and bladder capacity. During bladder overactivity by intravesical PGE 2 , micturition intervals, micturition volumes, and bladder capacity decreased in vehicle-and 1 mg/kg DFL23448-treated rats, but not in 10 mg/kg DFL23448-treated rats. Bladder pressures increased less in rats treated with DFL23448 10 mg/kg than in vehicle-or 1 mg/kg DFL23448-treated rats. DFL23448 (10 mg/kg i.v.), but not vehicle, prevented cold stress-induced bladder overactivity. Our results support a role for bladder TRPM8-mediated signals in experimental bladder overactivity.

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“…Icilin is a cold-inducing compound that produces a behavioral stimulant effect comprised of WDS, hyperthermia, writhing, and excessive grooming in rats following intraperitoneal injection (Collier, 1974; Wei, 1976, 1981; Collier et al, 1981; Cowan and Watson, 1978; Cowan, 1981; Werkheiser et al, 2006, 2007, 2009; Ding et al, 2008). Consistent with prior work, icilin elicited a dose-dependent increase in shaking behavior in rats in the present experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the potential of TRPM8 ligands as analgesic, antipruritic and antiarthritic agents, the endogenous and exogenous substances that modulate their pharmacological effects in vivo are largely unknown. The trademark overt pharmacological effect of icilin in rats is vigorous wet-dog shakes (WDS) (Wei, 1976, 1981; Werkheiser et al, 2006, 2007, 2009), and this shaking behavior provides a sensitive, reproducible, and quantifiable endpoint to investigate TRPM8 pharmacology in vivo and to identify, and exclude, receptor systems that shape the pharmacological response to TRPM8 channel activation.…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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Icilin-evoked behavioral stimulation is attenuated by alpha2-adrenoceptor activation

et al. 2011

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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 alpha2-adrenoceptor activation inhibits icilin-induced WDS. Rats injected with icilin (0.5, 1, 2.5, 5 mg/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 (2.5 mg/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 alpha2-adrenoceptor agonist, ST91 (0.075, 0.15 mg/kg), also decreased the incidence of shaking elicited by 2.5 mg/kg of icilin. Pretreatment with yohimbine (2 mg/kg, i.p.) enhanced the shaking induced by a low dose of icilin (0.5 mg/kg). The imidazoline site agonists, agmatine (150 mg/kg, i.p.) and 2-BFI (7 mg/kg, i.p.), did not affect icilin-evoked shaking. These results suggest that alpha2-adrenoceptor activation inhibits shaking induced by icilin and that increases in peripheral, as well as central, alpha2-adrenoceptor signaling oppose the behavioral stimulant effect of icilin.

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

Cited by 11 publications

References 51 publications

Nitric oxide in central amygdala potentiates expression of conditioned withdrawal induced by morphine

Nitric oxide in central amygdala potentiates expression of conditioned withdrawal induced by morphine

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

Icilin-evoked behavioral stimulation is attenuated by alpha2-adrenoceptor activation

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