The osteoarthritis associated sphingolipid sphingomyelin 34:1 causes inflammatory pain in mice

Osteoarthritis (OA) has a multifactorial pathogenesis, pain being the main symptom driving clinical decision making. Dysregulation of multiple mediators occurs in OA, the roles of many remaining to be identified. In dogs and humans with OA, synovial fluid lipidome dysregulation occurs, some findings being replicated in the plasma lipidome in a mouse OA model. One upregulated lipid is the sphingomyelin N-palmitoyl-D-erythro-sphingosylphosphorylcholine (d18:1/16:0), referred to here as SM. This study aimed to determine if SM causes joint pain and neuronal hyperexcitability in mice.

The effects of SM or a structurally related ceramide (CM) on mouse sensory neuron excitability were measured using patch-clamp electrophysiology, as well as the ability of intraarticular SM and CM to induce inflammatory pain in mice.

Incubation of sensory neurons with 1 µM SM decreased rheobase, compared to incubation with vehicle (p-adj = 0.0000146, 95 % confidence interval (CI): 50.20, 76.73 pA) or CM (p-adj = 0.138, CI: 103.45, 171.55 pA). Similarly, SM induced mechanical hypersensitivity in mice compared to mice receiving vehicle (p-adj = 0.000003, 95 % confidence interval (CI): 166.82, 251.63 g) or CM (p-adj = 0.055, 95 % CI: 218.28, 268.12 g), which was coupled with a significant decrease in rheobase of knee-innervating neurons isolated from SM-injected mice compared to those receiving vehicle (p-adj = 0.0138, CI: 50.19, 76.73 pA) or CM (p-adj = 1.0, CI: 103.45, 171.55 pA).

The results generated demonstrate that a dysregulated lipidome can contribute to inflammatory OA pain, further work being necessary to determine the mechanism by which SM exerts its activity.