Diabetic distal symmetric polyneuropathy (DSP) is the presence of symptoms and signs of nerve damage/dysfunction that may occur in people with diabetes. Typical symptoms include chronic pain and numbness, particularly in the hands and feet. Risk factors for the development of painful DSP include obesity, poor control of diabetes and female sex. The cause of DSP is due to damage to small blood vessels caused by prolonged high blood sugar levels. However, it is not known what causes some people to experience pain, whilst others are only affected by numbness or other sensory changes.
Recent evidence shows that low-grade systemic inflammation is related to the severity of neuropathy and neuropathic pain in a subgroup of patients with diabetic DSP recruited in the Pain in Neuropathy Study (PiNS). Furthermore, there is a potential physiological link between inflammation and the endocannabinoid system – a receptor system expressed throughout the central nervous and immune systems. The authors of a recent biomarker study therefore aimed to analyse the associations between endocannabinoids and related lipids measured in serum and pain in PiNS participants.
The Endocannabinoid System
The endocannabinoid system (ECS) includes a heterogeneous group of lipid messengers known as endocannabinoids (eCBs). The best-known endocannabinoids are N-arachidonoylethanolamine (AEA, also known as anandamide) and 2-arachidonoylglycerol (2-AG). These messengers activate receptors (CB1 and CB2) and are believed to be involved in several important cognitive and physiological functions – including inflammation. The ECS also includes lipid mediators that are structurally and functionally related to eCBs but do not target CB receptors, namely, N-acylethanolamines such as oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and stearoylethanolamide (SEA).
Whilst there is some evidence to support the effects of cannabinoids on inflammation and transmission of pain signals, there remains a paucity of evidence supporting the safety and effectiveness of cannabis-based medicines for the treatment of chronic pain in everyday clinical practice.
Design and Methods of the Study
A total of 170 participants from the PiNS, an observational, cross-sectional, multicentre study in which patients with painless or painful DSP underwent deep phenotyping. Participants included in the present study were those for whom serum samples and neuropathic pain grading according to IASP/NeuPSIG were available. The researchers applied the NeupSIG grading system for neuropathic pain to assess pain in the feet as the plausible anatomical distribution when separating those with painful vs painless diabetic neuropathy.
A 10 ml non-fasting blood sample was drawn from each participant at the end of the clinic visit once all other procedures were completed. The blood was left to clot and centrifuged, resulting in the serum for testing. The lipid mediators were analysed in serum samples using liquid chromatography tandem mass spectrometry. Selected reaction monitoring (SRM) was used for the targeted lipid analysis using MS/MS transitions for AEA, OEA, PEA, SEA, and 2-AG.
Results of the Study
Analysis was conducted on serum samples from 79 and 91 participants from the painless neuropathy and painful neuropathy groups, respectively. The key finding of the study was that serum levels of AEA were higher in the painful neuropathy group.
The relationships between each lipid were examined and the strongest relationship was seen between levels of PEA and OEA.
The authors looked to assess the relationship between multiple endocannabinoids and related lipids by using a technique known as clustering. This clustering approach led to the creation of two clusters with low and high concentrations of eCBs respectively.
61% of individuals in the cluster of participants with high eCB levels had painful neuropathy compared with 45% of the group with low eCB levels.
The findings of this study show that high serum levels of five endocannabinoids or endocannabinoid-like lipids, and AEA in particular, were associated with painful DSP. This was consistent with the researchers’ hypothesis that eCBs would be raised in painful vs painless DSP – although the effect sizes were small.
AEA is a partial agonist at cannabinoid receptors, with its affinity for CB1 (mainly expressed in the central nervous system) being around four times higher than that of CB2 (mainly found in the immune system). The finding of altered levels of endocannabinoids such as AEA in chronic neurological disorders may be viewed as either a maladaptive mechanism contributing to disease, or as an adaptive response aimed at restoring homeostasis. However, as AEA is generally considered to be an antinociceptive, the researchers speculate that higher levels of AEA in this case likely represent a compensatory mechanism.
However, while this theory may make sense physiologically, the authors concede some limitations in the present study, including the small effect sizes and the issue of possible confounders. They conclude that, while this study demonstrates an association between painful neuropathy and elevated levels of cannabinoids and related lipids, the relevance of these findings to the search for analgesics targeting the endocannabinoid system needs to be determined in future studies.