Background & Aims
Spinal Muscle atrophy (SMA) is a rare genetic disorder affecting the spinal motor neuron, leading to muscle weakness and atrophy. SMA is frequently associated with chronic pain [1-3], and a growing population of patients with SMA raises the need for more effective pain management. However, there is very limited information about the underlying mechanisms of chronic pain in SMA, hampering the development of effective treatments. To improve our understanding of the molecular mechanisms underlying pain in SMA, we performed metabolomics of the cerebrospinal fluid (CSF) in thoroughly phenotyped patients with SMA. Based on previous studies in other musculoskeletal pain conditions [4-7], we primarily focused on amino acid metabolism including brain-chained amino acids (BCAA), urea cycle, and glutamate metabolism.
Methods
Thirteen adults with SMA receiving routine intrathecal Nusinersen treatment were recruited. Patient self-report outcomes included widespread pain index, average pain of last week, pain intensity at the time of testing, and pain interference. For somatosensory phenotyping, pain facilitation and mechanical pain sensitivity were assessed by temporal summation effect (TS) and pain pressure threshold (PPT), respectively. CSF samples were collected before Nusinersen injection, and 1H-NMR metabolomics analysis was used to identify and quantify metabolites. For the statistical analyses, we selected 5 metabolites: 3-hydroxybutyrate, glutamine, 2-oxoisocaproate, ornithine, acetyl-carnitine – and 5 pain measurements: widespread pain index, pain intensity at the time of testing, pain interference (with general activities, enjoyment of life, falling and staying asleep), TS, and PPT. Each metabolite was correlated with each pain measure using Pearson correlation.
Results
We report analyses that yielded correlation coefficients r>0.5 and p-values ?0.05. We found positive correlations between pain intensity at the time of testing and the level of 3-hydroxybutyrate (r=0.55, p=0.05), 2-oxoisocaproate (r=0.59, p=0.03), ornithine (r=0.69, p=0.01), and acetyl-carnitine (r=0.58, p=0.04), as well as between pain interference and 3-hydroxybutyrate (r=0.71, p=0.03), 2-oxoisocaproate (r=0.70, p=0.04), ornithine (r=0.83, p=0.006), and acetyl-carnitine (r=0.80, p=0.01). In addition, we found a negative correlation between glutamine and TS (r= -0.73, p=0.004).
Conclusions
The positive correlations of acetyl-carnitine and 3-hydroxybutyrate with pain measures are suggestive of an increasing shift of energy source to fatty acid degradation in the central nervous system (CNS) with increasing pain. The positive correlation of pain with 2-oxoisocaproate and ornithine is suggestive of an association with increased BCAA catabolism. BCAAs are the main nitrogen source in the glutamine-glutamate cycle, and glutamine is a precursor of glutamate, which is a major pain excitatory neurotransmitter. We postulate that a higher demand for BCAAs is driven by upregulated glutamate synthesis, leading to pain facilitation. Assuming that glutamate synthesis is inversely correlated with concentrations of its precursor glutamine, the negative correlation between glutamine and TS that we have observed may imply a positive association between glutamate in the CNS and pain facilitation as assessed by TS.
References
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Presenting Author
Abby Pei-Ting Chiu
Poster Authors
Topics
- Specific Pain Conditions/Pain in Specific Populations: Muscle and Myofascial pain