March 2010: Cannabinoids inhibit and may prevent neuropathic pain in diabetes. (University of Calgary; Alberta, Canada)

First some background: According to the World Health Organization, more than 220 million people worldwide are living with diabetes. Within the United States, the National Diabetes Fact Sheet cites 23.6 million people, or 7.6% of the population, as currently living with diabetes; and an additional 1.6 million as diagnosed each year. There are two common forms of diabetes: type I and type II. Type I diabetes usually affects an individual at birth, as they are unable to produce insulin in sufficient quantity. Type II diabetes typically occurs later in an individual's life and reflects a decreased ability of cells to utilize insulin. Insulin is a hormone secreted from Beta cells of the pancreas mainly in response to increased glucose levels in the blood. Insulin acts to allow glucose to be taken up by cells in muscle, liver, and fat, and subsequently being converted into stored forms of energy. With the accompanying lack of insulin or its function in diabetes, glucose, the simplest form of sugar, accumulates in the bloodstream, leading to a multitude of pathologies including neuropathic pain. Hyperglycemia (elevated blood glucose) causes small blood vessels to uptake higher levels of glucose, leading to thicker as well as weaker blood vessel membranes. With these thicker blood vessels comes a reciprocal decrease in blood flow, leading to decreased oxygen levels in many organs, including the brain. The decreased oxygen levels in the brain decreases the conduction velocity of neurons and may cause structural changes in brain cells. Additionally, Hyperglycemia causes the upregulation of oxygen radicals as well as the activation of microglia, both of which can damage nerve cells. Microglia are a type of brain cell that act as immune cells of the brain, they respond to infections of the brain and spinal cord. However, their activation in diabetes causes them to release cytotoxic chemicals in absence of infection, which can damage nerve cells. This damage and structural change in nerve cells is thought to be responsible for the phenomenon of diabetic peripheral neuropathy. It has been previously shown that inhibiting microglial activation leads to a dissipation of neuropathic pain in mouse models of diabetes.* It is also well known that both neurons and microglial cells express cannabinoid receptors.

The new information: This experiment involved inducing diabetes in mice in the presence and absence of cannabinoid agonists and observing the mice over a course of 8 months. There were six main experimental groups, one of which diabetes was induced without cannabinoid treatment, serving as a control. In a second group, diabetes was induced in conjunction with cannabidiol treatment. It was found that in this second group, neuropathic pain did not develop over the course of 8 months and the levels of activated microglia in the spinal cord were greatly reduced compared to the control. Additionally, when cannabidiol treatment was stopped, the mice continued to show reduced microglia as well as no signs of neuropathic pain. A third and fourth group involved the induction of diabetes and treatment with both CB1 and CB2 cannabinoid receptor agonists once symptoms of neuropathic pain started. The results indicated that both CB1 and CB2 agonists inhibited the symptoms of neuropathic pain, but the pain returned after treatment was stopped. The last two groups involved treatment with CB1 and CB2 cannabinoid receptor antagonists, which block the effect of cannabinoids, and no change was seen in the levels of pain compared to the control group.

What this means: This experiment provided more evidence that cannabinoids may be used in the treatment of neuropathic pain. However, the novel information obtained is much more surprising. When treated with cannabidiol at the onset of diabetes, the diabetic mice did not have any symptoms of neuropathic pain even when treatment was stopped. This suggests that treatment with cannabidiol at the onset of diabetes may produce permanent protective changes for nerve cells. Therefore, cannabis could hypothetically be used short-term at the onset of type II diabetes in adults for lifetime or long-term prevention of diabetic peripheral neuropathy.

*Tsuda, M., et al. “Activation of Dorsal Horn Microglia Contributes to Diabetes-induced Tactile Allodynia via Extracellular Signal-regulated Protein Kinase Signaling.” Glia. 56.4(2008): 378-86.

Toth, C., et al. “Cannabinoid-mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain.” Molecular Pain. 6.16(2010).