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Neuropathic pain, glia and cannabis

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. These are the opening words of a brand new article on 'Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain' from the hand of Cory C Toth and colleagues. 

Glia, Cannabinoids and neuropathic pain 

The authors point out that current treatments  for neuropathic pain, have a focuss on blocking neurotransmission. This, they say, may limit their effectiveness as the concomitant production of many inflammatory mediators continues to activate nociceptive neurons, contributing to pain hypersensitivity. [1]

They bring in mind that neuropathic pain promote the presence of inflammatory mediators within the spinal cord. This leads to a great variety of pro-inflammatory cytokines in the medula and the dorsal sensory ganglion, such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα), All these infkammatory enhancers are produced by non-neuronal cells, such as with glial cells. Thus neuropathic pain currently is coined as gliopathic pain. 

Gliopathic pain 

Gliopathic pain, a new term! 

They follow their introduction stating that:

One important microglial system is the family of cannabinoid (CB) receptors and its endogenous ligands. Endocannabinoids modulate microglial cell migration without disturbing their ability to phagocytose particles or produce nitric oxide. Although endocannabinoids, including anandamide and 2-arachidonoylglycerol (2-AG) act upon CB1 and CB2 receptors are secreted by neurons, they are more prominently produced in microglial cells during neuroinflammatory conditions.

The authors studied clinically available dugs for neuropathic pain to detect their impact upon microglial activation in an animal model of chronic neuropathic pain. Mice receiving intranasal/intraperitoneal cannabidiol demonstrated lower densities of microglia in the dorsal spinal cord. Diabetic mice receiving nabilone had amelioration of both tactile allodynia and thermal hyperalgesia. However the authors did not identify any obvious differences in qualitative assessment of microglial activation nor differences in electrophysiological detection of diabetic neuropathy.

So for the time being some biological readouts were positive, some effects wre seen for Cannabinoids on the level of glia cells, but a crisp picture did not yet appear.

Jan M. Keppel Hesselink, MD, PhD, october 2010 

Referentie

[1] Toth CC, Jedrzejewski NM, Ellis CL, Frey WH 2nd. | Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. | Mol Pain. | 2010 Mar 17;6:16.