| Neuropathic pain (NP) is a debilitating medical condition that affects an estimated 2 million people in the United States annually. Causes include central and peripheral nervous system trauma, post herpetic neuralgia, the painful neuropathy that often accompanies diabetic polyneuropathy and complications arising from viral infections. The hallmarks of neuropathic pain are allodynia and hyperalgesia; patients suffering from neuropathic pain often perceive non-noxious stimuli, such as a light touch, as painful and are hypersensitive to noxious stimuli. Whereas classical pain resolves as tissues heal, NP arises from injury to central and peripheral nerves and can persist for years. Currently, the treatment options for NP are opiates, tricyclic antidepressants, antiepileptics and NMDA antagonists. However, these treatments are associated with mediocre pain resolution and pose significant serious side effects.; This research project was designed to evaluate the role of sphingosine 1phosphate (S1P) and lysophosphatidic acid (LPA) signaling in the modulation of neuropathic pain. S1P and LPA signal through sets of specific G-protein coupled receptors, S1P1-5 and LPA1-5. Downstream signaling events include increased proliferation, differentiation, migration and survival. Recent studies have highlighted the role of S1P and LPA signaling in neuronal cells; S1P has been shown to increase neuronal excitability and LPA induces demyelination and pain after nerve injury.; Using the chronic constriction injury (CCI) model of neuropathic pain, we evaluated the efficacy of S1P agonist and LPA antagonist compounds to reduce the thermal hyperalgesia and mechanical allodynia after nerve injury in rats. Prophylactic treatment with S1P agonist compounds including VPC01091.1 and FTY720 was associated with reductions in measures of thermal hyperalgesia and mechanical allodynia. Further, therapeutic treatment with VPC01091.1 produced statistically significant reductions in mechanical allodynia and appeared to reduce thermal hyperalgesia after nerve injury. Similar to the S1P agonist compounds, prophylactic treatment with LPA antagonist compounds, VPC51299 and KI16425, also reduced thermal hyperalgesia and mechanical allodynia. Therapeutic treatment with VPC51299 was less efficacious at relieving these measures of neuropathic pain.; This is the first report that pan-S1P receptor agonists and LPA receptor antagonists are effective in reducing thermal hyperalgesia and mechanical allodynia associated with the CCI model of neuropathic pain. |
