Chronic neuropathic pain is a challenging condition that affects millions globally, often proving difficult to treat with current medications. Understanding the underlying biological changes in conditions like neuropathic pain is crucial for developing more effective treatments and better diagnostic tools. Recent research has explored specific molecular and biochemical alterations in the blood of individuals with chronic neuropathic pain, focusing on connections between lipid metabolism pathways and the body’s natural endocannabinoid system.
Understanding the Origins of Chronic Neuropathic Pain
Scientists are working to understand the complex mechanisms behind chronic neuropathic pain, which can stem from damage or dysfunction in the nervous system. While existing treatments can offer some short-term relief, they often come with unwanted side effects. This highlights the need for objective ways to diagnose chronic neuropathic pain and guide treatment choices.
A recent study, published in the European Journal of Clinical Investigation, aimed to identify biochemical changes in the blood of patients with chronic neuropathic pain. Researchers collected blood samples from two independent groups of individuals with neuropathic pain and pain-free controls in the UK and Ireland. They then investigated the relationship between these changes and various clinical measures of pain.
Design and Methods
Blood samples were collected across two independent sites in the UK and Ireland from a total of 129 patients with chronic neuropathic pain and 127 control participants.
Data for age, sex, mood, and anxiety were collected in addition to clinical pain-related data for chronic neuropathic pain participants.
Univariate analyses were performed, assessing the levels of endocannabinoids and related N‐acylethanolamines, gene expression and questionnaire data in patients with chronic neuropathic pain compared to controls.
Key Findings: Altered Lipid Metabolism and Endocannabinoids
The study uncovered several significant findings regarding the metabolic pathways involved in chronic neuropathic pain:
- CHPT1 Gene Upregulation: Gene expression analysis showed an increase in choline phosphotransferase 1 (CHPT1) in the blood of chronic neuropathic pain patients. CHPT1 plays a role in the Kennedy pathway, which is involved in the synthesis of phosphatidylcholine (PC).
- Reduced Phosphatidylcholine (PC) Levels: Despite the upregulation of CHPT1, levels of phosphatidylcholine (PC), a key molecule in cell membranes, were significantly decreased in the plasma of chronic neuropathic pain patients. This unexpected finding suggests that PC might be rapidly used or converted into other signaling molecules in individuals with chronic neuropathic pain. Decreased PC levels have also been observed in other chronic pain conditions, potentially leading to mitochondrial dysfunction, which impacts energy metabolism and nerve activity.
- Increased 2-Arachidonoylglycerol (2-AG) Levels: The study found significantly higher levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the plasma of neuropathic pain patients compared to controls.
- Changes in Endocannabinoid System Genes: The expression of genes involved in breaking down endocannabinoids also supported the increase in 2-AG. Specifically, monoacylglycerol lipase (MAGL) and N-acylphosphatidylethanolamine phospholipase D (NAPEPLD), enzymes involved in endocannabinoid metabolism, were found to be downregulated in chronic neuropathic pain. This downregulation could contribute to higher levels of endocannabinoids like 2-AG.
- Levels of the endocannabinoid anandamide (AEA) and related N‐acylethanolamines, N-palmitoylethanolamide (PEA) and N-oleoylethanolamine (OEA), were found to be highly mutually correlated. In comparison, levels of 2-AG were not substantially correlated with AEA, PEA, or OEA.
In addition to changes in metabolic pathways, this study found differences in self-reported mental health between individuals with and without chronic neuropathic pain:
- Depression and anxiety scores were significantly higher in patients with chronic neuropathic pain compared to healthy controls: 76.3% of patients with neuropathic pain were classified as having mild to severe depression compared to 12.9% of controls.
The Endocannabinoid System: A Potential Compensatory Response
The increase in plasma 2-AG levels in CNP patients might represent a compensatory mechanism by the body to help regulate pain. Endocannabinoids like 2-AG and AEA interact with cannabinoid receptors (CB1 and CB2) located throughout the body, including areas involved in pain signalling. This interaction can help reduce pain sensations through various mechanisms, such as influencing nerve activity and modulating the body’s inflammatory response.
Conversely, our research blog last week covered a newly identified mechanism of action for the analgesic effect of paracetamol, which indicated that paracetamol reduced 2-AG synthesis, and it was via this mechanism that contributed to paracetamol’s pain-relieving effects. Consequently, more work is required to fully understand the role of 2-AG in chronic pain and whether its increase is truly a compensatory mechanism or is a contributing factor to the development and maintenance of pain.
The study also confirmed that factors such as age, sex, depression, and anxiety had strong associations with chronic neuropathic pain. Depression and anxiety are common alongside chronic pain of all types, and the research suggests a complex interplay between these conditions and alterations in lipid metabolism pathways.
What Does This Mean For Patients?
These findings suggest that changes in lipid metabolism, particularly within the Kennedy and endocannabinoid pathways, are connected to chronic neuropathic pain. This research highlights several potential new areas for:
- Biomarker Development: Identifying specific molecular changes in the blood could lead to new diagnostic tools for chronic neuropathic pain.
- Novel Analgesic Targets: The enzymes and pathways involved could become targets for developing new pain medications that work differently from existing treatments.
While more research is needed, this study provides valuable insights into the biological underpinnings of chronic neuropathic pain. Understanding these complex processes is a crucial step towards improving patient care and developing more effective strategies for managing chronic pain.
Disclaimer: This blog post is based on scientific research and should not be taken as medical advice. Always consult with a healthcare professional for any health concerns or before making any decisions related to your health or treatment.
