Peripheral participation of cholecystokinin in the morphine-induced peripheral antinociceptive effect in non-diabetic and diabetic rats

Laboratorio Mecanismos del Dolor, Centro de Investigación y Posgrado, División Académica de Ciencias de la Salud, Universidad Juárez Autónoma de Tabasco, Villahermosa, Tabasco, Mexico.
Neuropharmacology (Impact Factor: 5.11). 04/2007; 52(3):788-95. DOI: 10.1016/j.neuropharm.2006.09.015
Source: PubMed


The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.

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    • "To determine the antihyperalgesic role of 7-hydroxy-3,4-dihydrocadalin, the formalin test was performed as described elsewhere [28]. Streptozotocin-induced diabetic rats (after 3 weeks) were placed in open observation chambers for 30 min to allow them to acclimate to their surroundings; then they were removed and gently restrained while the dorsum of the hind paw was injected with 50 μL of 0.5% formalin using a 30-gauge needle. "
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    ABSTRACT: Painful neuropathy is the most common and debilitating complication of diabetes and results in hyperalgesia and allodynia. Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy. Current therapeutic approaches are only partially successful and they are only thought to reduce the pain associated with peripheral neuropathy. Some natural products offer combined antioxidant, anti-inflammatory and antinociceptive properties that may help to treat in a more integrative manner this condition. In this regard, the purpose of this study was to investigate the antineuropathic effect of 7-hydroxy-3,4-dihydrocadalin in streptozotocin-induced diabetic rats and mice without glucose control as well as the possible mechanism of action involved in this effect. Rats and mice were injected with 50 or 200 mg/kg streptozotocin, respectively, to produce hyperglycemia. The formalin test and von Frey filaments were used to assess the nociceptive activity. Rota-rod was utilized to measure motor activity and malondialdehyde assay to determine anti-oxidative properties. After 3 weeks of diabetes induction, chemical hyperalgesia was observed in streptozotocin-injected rats. Oral acute administration of 7-hydroxy-3,4-dihydrocadalin (0.3-30 mg/kg) decreased in a dose-dependent manner formalin-evoked hyperalgesia in diabetic rats. In addition, methiothepin (non-selective 5-HT receptor antagonist, 1 mg/kg, i.p.) and ODQ (guanylate cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (opioid receptor antagonist, 1 mg/kg, s.c.), prevented 7-hydroxy-3,4-dihydrocadalin-induced antihyperalgesic effect. The anti-hyperalgesic effect of 7-hydroxy-3,4-dihydrocadalin was similar to that produced by pregabalin (10 mg/kg, p.o.). Furthermore, oral acute administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) reduced streptozotocin-induced changes in malondialdehyde concentration from plasma samples. Unlike pregabalin, 7-hydroxy-3,4-dihydrocadalin did not affect motor activity. Six weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. At this time, oral administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) or pregabalin (10 mg/kg) reduced in a similar way tactile allodynia in diabetic rats. Finally, chronic oral administration of 7-hydroxy-3,4-dihydrocadalin (30-300 mg/kg, 3 times/week, during 6 weeks), significantly prevented the development of mechanical hyperalgesia and allodynia in streptozotocin-induced diabetic mice. Data suggests that 7-hydroxy-3,4-dihydrocadalin has acute and chronic effects in painful diabetic neuropathy. This effect seems to involve antioxidant properties as well as activation of 5-HT receptors and inhibition of guanylate cyclase enzyme.
    BMC Complementary and Alternative Medicine 04/2014; 14(1):129. DOI:10.1186/1472-6882-14-129 · 2.02 Impact Factor
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    • "showing that streptozotocin-induced experimental diabetes produces a state of nociceptive sensitization (Malmberg et al., 2006; Torres-López et al., 2007; Arreola-Espino et al., 2007; Jiménez-Andrade et al., 2008). "
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    ABSTRACT: Aims: The purpose of this study was to investigate the antinociceptive effect of epicatechin as well as the possible mechanisms of action in diabetic rats. Main methods: Rats were injected with streptozotocin to produce hyperglycemia. The formalin test was used to assess the nociceptive activity. Key findings: Acute pre-treatment with epicatechin (0.03-30 mg/kg, i.p.) prevented formalin-induced nociception in diabetic rats. Furthermore, daily or every other day treatment for 2 weeks with epicatechin (0.03-30 mg/kg, i.p.) also prevented formalin-induced nociception in diabetic rats. Acute epicatechin-induced antinociception was prevented by l-NAME (N(ω)-nitro-l-arginine methyl ester hydrochloride, 1-10mg/kg, non-selective nitric oxide synthesis inhibitor), 7-nitroindazole (0.1-1mg/kg, selective neuronal nitric oxide synthesis inhibitor), ODQ (1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one, 0.2-2mg/kg, guanylyl cyclase inhibitor) or glibenclamide (1-10mg/kg, ATP-sensitive K(+) channel blocker). Moreover, epicatechin (3mg/kg)-induced antinociception was fully prevented by methiothepin (0.1-1mg/kg, serotonergic receptor antagonist), WAY-100635 (0.03-0.3mg/kg, selective 5-HT1A receptor antagonist) or SB-224289 (0.03-0.3mg/kg, selective 5-HT1B receptor antagonist). In contrast, BRL-15572 (0.03-0.3mg/kg, selective 5-HT1D receptor antagonist) only slightly prevented the antinociceptive effect of epicatechin. Naloxone (0.1-1mg/kg, opioid antagonist) did not modify epicatechin's effect. Significance: Data suggest the involvement of the nitric oxide-cyclic GMP-K(+) channel pathway as well as activation of 5-HT1A and 5HT1B, and at a lesser extent, 5-HT1D, but not opioid, receptors in the antinociceptive effect of epicatechin in diabetic rats. Our data suggest that acute or chronic treatment with epicatechin may prove to be effective to treat nociceptive hypersensitivity in diabetic patients.
    Life sciences 09/2013; 93(17). DOI:10.1016/j.lfs.2013.08.022 · 2.70 Impact Factor
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    • "Diabetic neuropathic pain (DNP) is often resistant to non-steroidal anti-inflammatory drugs (NSAIDs) and, in many cases, even opioids do not provide sufficient pain relief. Indeed, STZ-treated rats have consistently shown to be hypo-responsive to the antinociceptive effects of morphine (Otto et al., 2011b; Taliyan and Sharma, 2012; Torres-Ló pez et al., 2007). Currently, anticonvulsants, such as pregabalin (PGB) and gabapentin, and antidepressants, such as amitriptyline and duloxetine, are often used for the management of DNP (Yamamoto et al., 2009). "
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    ABSTRACT: Peripheral neuropathy is a common complication of diabetes and is often accompanied by episodes of pain. There is evidence that diabetic neuropathy may affect the trigeminal nerve, altering the transmission of orofacial sensory information. Structural changes in the trigeminal ganglia may be involved in the development of these sensory alterations. Herein, we evaluate the development of orofacial sensory changes after streptozotocin-induced diabetes in rats, and their sensitivity to pregabalin and morphine treatments. Furthermore, stereological analysis of the trigeminal ganglia was performed. Diabetic rats showed similar responses to 1% formalin applied into the upper lip compared to normoglycemic rats on weeks 1, 2 and 4 after streptozotocin. Additionally, there was no difference in the facial mechanical threshold of normoglycemic and diabetic rats, on weeks 1 up to 5 after streptozotocin, while the paw mechanical threshold of diabetic rats was significantly reduced. In contrast, diabetic rats developed long-lasting orofacial heat and cold hyperalgesia. Moreover, stereological analyses revealed significant neuronal loss in the trigeminal ganglia of diabetic compared to normoglycemic rats. Pregabalin treatment (30mg/kg, p.o.) of diabetic rats resulted in marked and prolonged (up to 6h) reduction of heat and cold orofacial hyperalgesia. Likewise, morphine treatment (2.5mg/kg, s.c.) abolished orofacial heat and cold hyperalgesia, but its effect was significant only up to 1h after the administration. In conclusion, the results of the present study demonstrated that streptozotocin-treated rats developed long-lasting orofacial heat and cold hyperalgesia, which is more amenable to reduction by pregabalin than morphine.
    Brain research 01/2013; 1501. DOI:10.1016/j.brainres.2013.01.002 · 2.84 Impact Factor
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