Department of Clinical Neurosciences and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Mol Pain. 2010 Mar 17;6:16. doi: 10.1186/1744-8069-6-16.
Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state.
Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists.
The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state.
尽管糖尿病及其与糖尿病周围神经病变（DPN）和神经病理性疼痛（NeP）的关系很常见，但我们对导致糖尿病慢性疼痛的潜在机制仍知之甚少。最近的证据表明，小胶质细胞在神经病理性疼痛状态中起着重要作用。一种潜在的治疗选择是大麻素，其大麻素受体（CB）在神经元和小胶质细胞上表达。我们研究了链脲佐菌素（STZ）-糖尿病 CD1 小鼠脊髓和丘脑小胶质细胞的积累和激活，以及在慢性 NeP 状态发展过程中大麻素受体激动剂/拮抗剂的影响。我们在糖尿病起始时以及糖尿病及其相关 NeP 状态建立后，以多种剂量向糖尿病小鼠鼻内或腹腔内给予大麻素激动剂/拮抗剂。
在没有干预的情况下，糖尿病小鼠在 8 个月内出现触觉过敏和热敏性。在背根脊髓和丘脑核中观察到小胶质细胞密度增加，并伴有磷酸化 p38 MAPK 的升高，这是小胶质细胞激活的标志物。当与糖尿病同时开始时，中高剂量鼻内大麻二酚（大麻素受体 2 激动剂）和腹腔内大麻二酚减弱了 NeP 状态的发展，即使在其停止后，也不会改变糖尿病状态。大麻二酚还与背根脊髓中小胶质细胞密度升高和磷酸化 p38 MAPK 升高的限制有关。当在已建立的 DPN NeP 状态中开始时，CB1 和 CB2 激动剂均表现出镇痛作用，直到其停止。CB1 和 CB2 拮抗剂均未表现出促痛作用。
背根脊髓中小胶质细胞积累和激活的预防与神经病理性疼痛状态的有限发展有关。大麻素在这种糖尿病小鼠模型中表现出镇痛作用。这些结果表明，这种干预措施也可能使患有 DPN 的人类受益，并且早期引入也可能改变 NeP 状态的发展。
