Leveraging Neuroinflammation Responses To Treat Pain Using Micellar Formulations Informed By Secretory Phospholipase A2 Responses In Neuropathy

Sonia Kartha, University of Pennsylvania

Abstract

Despite the high prevalence of chronic neuropathic pain, effective treatment strategies remain lacking. This is due to an incomplete understanding of the complex interactions of immune and neuronal mechanisms leading to the spinal neuronal hyperexcitability that establishes and maintains persistent pain states. Current neuropathic pain treatments like neuromodulatory drugs, which reduce neuronal hyperexcitability by non-specifically suppressing neuronal activity, require high repeated systemic dosing, that can lead to substantial off-target toxicity due to challenges with effective delivery. These obstacles underscore the need to identify improved mechanistic targets involved in neuropathic pain and platforms to deliver therapeutics that can localize delivery to the sites of nociceptive transmission. In addition to inciting inflammation, inflammatory mediators such as secreted phospholipase A2 (sPLA2), can directly regulate spinal glutamatergic signaling and hyperexcitability through its generation of lipid mediators. Although early increases in sPLA2 are implicated in several painful neuropathies, it is not known if, or where, sPLA2 may contribute to pain after nerve root injury. Studies in this thesis characterize sPLA2 expression after a painful neve root compression and use systemic and spinal sPLA2 inhibition to define its inflammatory and neuromodulatory roles in the initiation and maintenance of neuropathic pain. As hydrolytic enzymes, sPLA2 activity can also be leveraged to directly deliver and release encapsulated drugs from sPLA2-responsive phospholipid micelles to areas of nociception. Therefore, the feasibility and effectiveness of encapsulating sPLA2 inhibitors and the neuromodulatory drug MPEP, into sPLA2-responsive and polymeric micelles are also assessed after painful nerve root compression in order to evaluate if these delivery platforms improve therapeutic effectiveness. Both peripheral and spinal sPLA2 expression increases with pain after root compression and together appear to initiate neuropathic pain and neuronal hyperexcitability by enhancing spinal inflammation. Later after injury, spinal sPLA2 maintains neuropathic pain by exacerbating spinal glutamatergic neurotransmission. Utilizing both sPLA2-inhibitor loaded micelles and MPEP loaded increase the effectiveness of both therapeutics by localizing delivery and increasing circulation time in vivo. Collectively, studies in this thesis establish sPLA2 as a potential target for treating painful neuropathy and provide evidence of the effectiveness of micellar delivery platforms to improve the utility of pain therapeutics.