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Characterization of Cannabinoid-Induced Relief of Neuropathic Pain in Rat Models of Type 1 and Type 2 Diabetes

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Characterization of Cannabinoid-Induced Relief of Neuropathic Pain in Rat Models of Type 1 and Type 2 Diabetes Characterization of cannabinoid-induced relief of neuropathic pain in rat models of type 1 and type 2 diabetes Gema Vera, Visitación López-Miranda, Esperanza Herradón, María Isabel Martín, Raquel Abalo ⁎ Departamento de Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos., Avda. de Atenas s/n, 28922 Alcorcón, Madrid, Spain article info abstract Article history: Diabetic neuropathy is a frequent complication of diabetes mellitus with a tremendous impact on patients' qual- Received 20 October 2011 ity of life, and it remains poorly treated. Cannabinoids relieve the signs of diabetic neuropathy in different ex- Received in revised form 21 April 2012 perimental models, including streptozotocin- (STZ-) induced type 1 diabetic rodents, and they may also Accepted 12 May 2012 relieve neuropathic signs in type 2 diabetic animals. This study compares the effect of the non-selective canna- Available online 17 May 2012 binoid agonist WIN 55,212-2 (WIN) in Zucker Diabetic Fatty (ZDF) rats (type 2 diabetes) and in STZ-injected Wistar rats (type 1 diabetes). Keywords: Cannabinoid WIN (or its vehicle) was either systemically administered at a non-psychoactive dose or locally injected. Neuropathic pain Selective CB1 and CB2 cannabinoid antagonists were used to characterize WIN antineuropathic effects. Type 2 diabetes Both type 1 and type 2 diabetic rats showed mechanical allodynia but not thermal hyperalgesia. WIN alleviated Zucker Diabetic Fatty rat mechanical allodynia in both models of diabetes. In STZ-treated rats, both cannabinoid receptors were involved, Type 1 diabetes whereas in ZDF rats, WIN effects seemed to mainly involve the activation of CB1 receptors. Higher doses of WIN Streptozotocin were needed to significantly relieve mechanical allodynia upon intraplantar administration in ZDF vs. STZ-injected rats. Cannabinoids, acting on systemic and/or peripheral receptors, may serve as a new therapeutic alternative for symptom management in painful neuropathy associated with both type 1 and type 2 diabetes. Additionally, our results highlight the need for appropriate selection of diabetic experimental models because the results from studies in STZ-induced diabetic rodents might not be applicable in all diabetic situations. © 2012 Elsevier Inc. All rights reserved. 1. Introduction is limited by their psychoactive properties, mediated by cannabinoid receptors expressed in the central nervous system (CNS). One way Diabetic neuropathies are among the most frequent complications to dissociate cannabinoid analgesia from the psychoactive effects is of diabetes mellitus (Aring et al., 2005) and have a tremendous impact to target cannabinoid receptors type 1 (CB1R) located in peripheral on patients' quality of life. Patients with diabetic sensory neuropathy nerve fibers (Karst and Wippermann, 2009). Topical application of experience a variety of aberrant sensations including spontaneous cannabinoids has reduced pain in a human experimental model pain, hyperalgesia (increased pain from a stimulus that normally (Rukwied et al., 2003). In animal models, local administration of provokes pain) and allodynia (pain due to a stimulus that does not nor- CB1R agonists has been reported to produce anti-nociceptive effects mally provoke pain, like the touch of clothes or bed sheets) (IASP in both inflammatory and neuropathic conditions (Fox et al., 2001; taxonomy; Vinik et al., 1995). Nackley et al., 2003; Richardson et al., 1998). The prevalence of neuropathy in diabetic patients may vary Most preclinical studies for diabetic neuropathy have been carried between studies (50–60%, Talbot et al., 2010; 16%, Bril et al., 2011). out in streptozotocin- (STZ-, a pancreatic beta-cell cytotoxin) induced It is frequently unreported (12.5%) and more frequently untreated diabetic rodents. These rodents develop a syndrome that resembles (39%) (Bril et al., 2011). Furthermore, although effective treatments type 1 diabetes. Cannabinoids have been tested in this model of dia- for diabetic neuropathy are available (see Bril et al., 2011; Smith betes (Doğrul et al., 2004; Ulugol et al., 2004; Bujalska, 2008). In and Argoff, 2011), many have side effects that limit their usefulness. STZ-induced diabetic rats, the non-selective cannabinoid agonist Therefore, alternative therapies are still needed. WIN 55,212-2 (WIN) reduced mechanical allodynia and hyperalgesia The cannabinoid system is one of the endogenous systems that (Ulugol et al., 2004; Bujalska, 2008). modulate pain perception. However, the clinical use of cannabinoids Several preclinical studies have examined diabetic neuropathy in type 2 diabetic animals (Otto et al., 2011; Oltman et al., 2008; Romanovsky et al., 2008). These models are important in the studies ⁎ Corresponding author. Tel.: +34 91 488 88 54; fax: +34 91 488 89 55. of diabetic complications. In adult humans, type 2 diabetes accounts E-mail address: [email protected] (R. Abalo). for about 90% to 95% of all diagnosed cases of diabetes (National 0091-3057/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2012.05.008 336 G. Vera et al. / Pharmacology, Biochemistry and Behavior 102 (2012) 335–343 Diabetes Statistics, 2011). Animal studies of type 2 diabetes can The occurrence of neuropathic signs (mechanical allodynia, heat provide useful information on the progression of nerve dysfunction hyperalgesia) was monitored on days 21 and 28 post-injection in diabetic patients (Shaikh and Somani, 2010). To our knowledge, (type 1 diabetes; Bujalska, 2008)orat7–8, 12–13 and 16–17 weeks no study has been carried out to test the antinociceptive effect of can- of age (type 2 diabetes). nabinoids in an animal model of type 2 diabetes, such as the Zucker Mechanical sensitivity was assessed using an electronic Von Frey Diabetic Fatty (ZDF) rat. apparatus (EVF3, Bioseb, BP89, Chaville Cedez, France). Rats were Therefore, the aim of this work was to determine whether the placed individually on an elevated iron mesh in a clear plastic cage non-selective cannabinoid agonist WIN 55,212-2 (WIN) is able to and were allowed to adapt to the testing environment for at least alleviate the signs of sensory neuropathy associated with long-term 10 min. Using a filament connected to the Von Frey apparatus, a me- diabetes in ZDF rats. Additionally, the involvement of CB1 and CB2 re- chanical stimulus of increasing intensity was applied to the plantar ceptors was investigated. Furthermore, a parallel study was carried aspect of each hindpaw, through the mesh floor. The apparatus auto- out in STZ-injected rats. matically records the intensity of the stimulus that provokes the sud- den withdrawal of the paw, and has an upper cut-off limit of 50 g. The test was performed four times with an interstimulus interval of ap- 2. Methods proximately 1 min. The mean of the four trials was used for data anal- ysis. Mechanical allodynia was defined as a significant decrease in the The experiments in the present study were designed to minimize withdrawal threshold evoked by mechanical stimuli. the number of animals used and their suffering, and throughout the Heat-antinociception was tested using a 37370 plantar test appa- experimental procedure, the international ethic standards for pain- ratus (Ugo Basile, Comerio VA, Italy). The withdrawal latency from a inducing experiments in laboratory animals (Zimmermann, 1983) focused beam of radiant heat applied to the mid plantar surface of and the European Communities Council Directive (No. 86/609, Nov the hindpaws was recorded. The intensity of light was adjusted at 24, 1986) were followed. All animal procedures were reviewed and the start of the experiment such that the control average baseline la- approved by the Animal Care and Ethical Committee of Universidad tencies were about 8 s and a cut-off latency of 25 s was imposed. The Rey Juan Carlos. withdrawal latency of each paw was measured during three trials at 5 min intervals, and the mean of the three readings was used for 2.1. Models of diabetes and diabetic neuropathy data analysis. Animals were habituated to the corresponding test environments, Male Wistar rats (240–300 g) obtained from Harlan Laboratories two days before the experiment, by leaving them inside the recording (Barcelona, Spain) were used to induce type 1 diabetes. For type 2 di- device for ten minutes. abetes, obese diabetic male ZDF/crl-lepr/fa and control lean male fa/+ rats were purchased from Charles River Laboratories (Research 2.2. Evaluation of the cannabinoid antinociceptive effect in diabetic rats Models, Barcelona, Spain) and shipped to the Universidad Rey Juan Carlos at 6 weeks of age. On day 28 after STZ injection (type 1 diabetes), or at 16–17 weeks Upon arrival at our laboratory, animals were stored (2–4/cage) in of age (type 2 diabetes), three sets of experiments were carried out in standard transparent cages (60 cm×40 cm×20 cm) furnished with the diabetic rats to test and characterize the antinociceptive effect of wood shaving bedding, which was changed three times a week. WIN. First, in some rats a single dose of vehicle (1 ml/kg; n=7) or Cages were placed adjacent to each other, in a climate-controlled en- WIN (1 mg/kg; n=8) was intraperitoneally administered. Second, vironment (temperature=20 °C; humidity=60%) with a 12 h light/ some diabetic rats received an intraperitoneal (i.p.) injection of the 12 h dark cycle (lights on between 08:00 and 20:00 h). Animals had CB1 (AM251) or the CB2 (SR144528) antagonists (1 mg/kg; n=8 free access to standard laboratory rat chow (Harlan-Iberica: Wistar each group) 20 min prior to WIN/vehicle i.p. injection. The effect of rats) or Purina rat chow 5008 (Charles River: ZDF rats and their con- the drugs intraperitoneally administered was analyzed in both trols) and to sterile tap water. paws. Finally, some diabetic rats received an intraplantar (i.pl.) ad- One week after arrival to the laboratory, diabetes was induced in ministration of a single dose of vehicle (25 μl) or WIN (50 or Wistar rats by intraperitoneal administration of STZ at a dose of 100 μg) alone or 20 min after the intraperitoneal injection of either 60 mg/kg body weight (Suanarunsawat et al., 1999).
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