Patients with inflammatory, but not neuropathic, pain showed significantly elevated levels of shed Sez6 in the CSF compared with the control patients. In neither group were the CSF levels of Sez6 significantly correlated with reported pain scores. The lack of a strong correlation between various measures of inflammation and subjective measures of pain intensity has been previously reported19 and is likely attributable to the multifactorial nature of pain.1
Osteoarthritis (the most common diagnosis of the patients with IP) involves release of inflammatory mediators11 that are capable of sensitising peripheral nociceptors,3 resulting in a lower activation threshold and increased firing of centrally projecting afferent axons in the spinal cord, even with normally innocuous stimuli.10 Increased excitatory drive and local neuroinflammation, in turn, lead to central nervous system sensitisation,9,21 including exaggerated and persistent synaptic long-term potentiation.8 The known roles for Sez6 in the development and maintenance of excitatory synapses,18 and the upregulation of Sez6 mRNA levels during long-term potentiation induction,6 suggest that Sez6 may be involved in the activity-dependent chronification of pain and might explain the observed association between elevated Sez6 levels in the CSF and IP conditions.
Sez6 levels in IP samples seem to be segregating into 2 clusters. No obvious commonalities could be identified amongst patients with the highest Sez6 levels, although clearer patterns may emerge if the sample size were increased and/or serial samples were available. If medically indicated, analysing serial samples from individual patients would be preferable to single sample analysis, provided the protocol for repeated CSF collection was standardised. An important consideration, particularly for interpretation of the results presented here, is that levels of Aβ, itself a product of BACE1 activity, are known to vary diurnally as well as increasing with draw frequency.13
Medical biomarkers are important tools for identifying susceptibility to disease, predicting treatment success, and facilitating objective diagnoses.24 A quantitative proteomics study indicated that Sez6 levels in the CSF are elevated in myalgic encephalomyelitis/chronic fatigue syndrome23 and Sez6 is also implicated in psychiatric disorders, forming part of a CSF biomarker signature for schizophrenia, bipolar disorder, and major depressive disorder.14 Although all 3 Sez6 family protein members are found in the CSF, only one (Sez6L2) has been identified in blood plasma.22 With the enhanced sensitivity (compared with Western blot) of ELISA-based assays, currently under development for shed Sez6 proteins, detection of Sez6 in serum may soon become feasible.
The authors have no conflict of interest to declare.
This project was supported by NHMRC Project Grant GNT1099930 to J.M. Gunnersen, NHMRC GNT1091636 to L.E. Edgington-Mitchell, and by grants from the NIH (NS102722, DE026806, and DK118971) and the Department of Defense (W81XWH1810431) to N.W. Bunnett.
The authors thank Sophie Wallace, Research Manager of the Department of Anaesthesia and Perioperative Medicine at the Alfred Hospital, for provision of deidentified patient data.
Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PR9/A41.
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