TABLE 2.

The role of sphingolipid metabolism in diverse pain conditions.

Disease	Molecular targets	Effects
Morphine anti-injury tolerance	S1P	Continuous administration of morphine treatment activates metabolic mechanisms of S1P and S1PR1 signaling production in the CNS, leading to morphine tolerance
	Ceramide	Ceramide promotes morphine resistance to injury demonstrated that ceramide is an upstream signaling mediator of neuroimmune activation, and that inhibition of ceramide synthesis blocks morphine resistance to injury, a process that is achieved by intervening in nitrogen oxidative stress through peroxynitrite synthesis
	Ceramide	Ceramide also induces oxidative DNA damage and activation of the nuclear enzyme poly adenosine diphosphate-ribose polymerase (PARP) via the nitrite-mediated nitrogen oxidative stress pathway, leading to apoptosis and participation in tolerance generation
	S1P	S1P inhibitors have likewise been shown to block the development of morphine tolerance by improving neuroglial cell function and decreasing the associated proinflammatory cytokine production
	S1PR1	S1PR1 antagonists blocked the development of morphine tolerance and prevented morphine-induced neuropathic pain
Fabry disease (FD)	Sphingolipids	The accumulation of sphingolipids in the nervous system (mainly peripheral nerves and DRG) alters the morphology and function of neuronal cytosol and axon, and regulates the activity of ion channels, which leads to sensory abnormalities and chronic pain
	Gb3/Lyso-Gb3	Excess Gb3 and lyso-Gb3 in peripheral tissues have a direct sensitizing effect on neurons
	Lyso-Gb3	Lyso-Gb3 can be involved in sensitizing peripheral neurons by acting on voltage-dependent calcium channels
	Gb3	One study analysis confirmed that tumor necrosis factor gene expression was higher in FD patients than in controls, and it was also hypothesized that there is a feed-forward loop between tumor necrosis factor, Gb3, and FD-induced pain, in which tumor necrosis factor further stimulates Gb3 loading of neurons and alters the expression of pain-associated ion channels, thus contributing to the analgesic effect
	Gb3	Gb3 induces mechanical nociceptive hypersensitivity in mice by enhancing proNGF-p75NTR signaling
	Gb3	Higher Gb3 deposition in skin fibroblasts may promote the release of proinflammatory mediators through activation of the Notch1 signaling pathway, thereby creating a peripheral inflammatory environment that promotes sensitization of injury receptors
Cancer-related pain	S1P/S1PR1 axis	Paclitaxel-induced neuropathic pain is associated with activation of the S1P/S1PR1 axis
	S1P/S1PR1 axis	S1PR1 antagonists act by blocking spinal neuroinflammation through inhibition of the activation of NF-ɤB and MAPKs
	S1P/S1PR1 axis	Bortezomib treatment resulted in increased levels of ceramides, sphingomyelins, and S1P in DHSc, demonstrating that Bortezomib upregulates S1P by altering the ceramide metabolic pathway, leading to pain, and this process is accompanied by increases in tumor necrosis factor and IL-1β, as well as changes in glutamatergic synaptic activity
	S1P/S1PR1 axis	The S1P/S1PR1 axis mediates CIPN development by affecting the primary cellular substrate, astrocytes, and driving the corresponding neuroinflammation and changes in glutamatergic synaptic activity
	S1P/S1PR1 axis	Intrathecal and systemic administration of S1PR1 antagonists can reverse CIBP pain behavior
Multiple sclerosis (MS)	S1P	S1P has strong pro-inflammatory activity, and in a clinical study, elevated concentrations of S1P were detected in the cerebrospinal fluid of MS patients, suggesting that S1P is involved in MS-associated chronic inflammation
	S1P	FTY720 effectively ameliorated the symptoms of an experimental autoimmune encephalomyelitis (EAE) model. It was also revealed that its mechanism of action may include affecting lymphocyte trafficking and initial activation, thereby reducing spontaneous lymphocyte infiltration into inflammatory sites
	Ceramide/S1P	Disturbances in sphingolipid metabolism and abnormal accumulation of ceramide in astrocytes may be involved in the demyelination process by damaging oligodendrocytes