jwh-133 and Diabetes-Mellitus--Type-2

While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D). The goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)- dependent dilation of cerebral arterioles during T1D.. In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to an eNOS-dependent agonist (adenosine 5'-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-Daspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 hour following JWH-133 (1 mg/kg IP). In a second series of experiments, to determine the role of CB2 receptors, rats were injected with AM-630 (3 mg/kg IP). AM-630 has been shown to be a specific antagonist to CB2 receptors. After 30 minutes, the nondiabetic and T1D rats were treated with JWH-133 (1 mg/kg IP). One hour after the injection of JWH-133, responses of arterioles to the agonists were again examined. In a third series of experiments, a potential time-dependency in reactivity of cerebral arterioles to the agonists was examined. Initially responses of arterioles to ADP, NMDA and nitroglycerin were examined. Then, one hour after injection of vehicle (ethanol) for JWH-133 and AM-630 responses of arterioles to the agonists were again examined.. Baseline diameter of cerebral arterioles was similar in nondiabetic and T1D rats across all groups of rats. In addition, treatment of the rats with JWH-133, JWH-133 and AM-630 or vehicle (ethanol) did not produce a change in baseline diameter in either nondiabetic or T1D rats. Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in diabetic rats. Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and diabetic rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and diabetic rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors.. This study showed that acute treatment with a specific activator of CB2 receptors could potentiate dilation of cerebral resistance arterioles to eNOS- and nNOS-dependent agonists in both nondiabetic and T1D rats. In addition, the influence of activation of CB2 receptors on cerebral vascular function could be attenuated by treatment with a specific antagonist of CB2 receptors (AM-630). Based on these findings, one could speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular disease that can contribute to the pathogenesis of stroke.

Topics: Adenosine Diphosphate; Animals; Arterioles; Cannabinoid Receptor Agonists; Cannabinoids; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Ethanol; N-Methylaspartate; Nitric Oxide Synthase; Nitroglycerin; Rats; Rats, Sprague-Dawley; Vasodilation

The activation of the transcription factor Nrf2 inhibits neuropathy and modulates the activity of delta-opioid receptors (DOR) in type 2 diabetic mice but the impact of Nrf2/HO-1 pathway on the antinociceptive actions of cannabinoid 2 receptors (CB2R) has not been assessed. Using male mice BKS.Cg-m+/+Leprdb/J (db/db) we investigated if treatment with cobalt protoporphyrin IX (CoPP), an HO-1 inductor, inhibited mechanical allodynia, hyperglycemia and obesity associated to type 2 diabetes. The antinociceptive effects of JWH-015 and JWH-133 (CB2R agonists) administered with and without CoPP or sulforaphane (SFN), a Nrf2 transcription factor activator, have been also evaluated. The expression of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and c-Jun N-terminal kinase (JNK) in sciatic nerve and that of the CB2R on the dorsal root ganglia from animals treated with CoPP and/or SFN were assessed. CoPP treatment inhibited allodynia, hyperglycemia and body weight gain in db/db mice by enhancing HO-1/NQO1 levels and reducing JNK phosphorylation. Both CoPP and SFN improved the antiallodynic effects of JWH-015 and JWH-133 and expression of CB2R in db/db mice. Therefore, we concluded that the activation of antioxidant Nrf2/HO-1 pathway potentiate the effects of CB2R agonists and might be suitable for the treatment of painful neuropathy linked to type 2 diabetes.

Topics: Animals; Blood Glucose; Body Weight; Cannabinoid Receptor Agonists; Cannabinoids; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Models, Animal; Ganglia, Spinal; Heme Oxygenase-1; Hyperalgesia; Male; Mice; Mice, Transgenic; NF-E2-Related Factor 2; Protoporphyrins; Receptor, Cannabinoid, CB2; Sciatic Nerve