NGF-mediated photoablation of nociceptors reduces pain behavior in mice

Abstract

AbstractNerve growth factor (NGF) and its receptors TrkA and p75 play a key role in the development and function of peripheral nociceptive neurons. Here we describe novel technology to selectively photoablate TrkA positive nociceptors through delivery of a phototoxic agent coupled to an engineered NGF ligand and subsequent near infrared (NIR) illumination. We demonstrate that this approach allows for on demand and localized reversal of pain behaviors in mouse models of acute, inflammatory, neuropathic and joint pain. To target peripheral nociceptors we generated a SNAP-tagged NGF derivative, NGFR121Wthat binds to TrkA/p75 receptors but does not provoke signaling in TrkA positive cells or elicit pain behaviors in mice. NGFR121W-SNAPwas coupled to the photosensitizer IRDye®700DX phthalocyanine (IR700) and injected subcutaneously. Following NIR illumination of the injected area, behavioral responses to nociceptive mechanical and sustained thermal stimuli, but not innocuous stimuli, were substantially reduced. Similarly, in models of inflammatory, osteoarthritic and neuropathic pain, mechanical hypersensitivity was abolished for three weeks following a single treatment regime. We demonstrate that this loss of pain behavior coincides with the retraction of neurons from the skin which then re-innervate the epidermis after 3 weeks corresponding with the return of mechanical hypersensitivity. Thus NGFR121W-SNAP-mediated photoablation is a minimally invasive approach to reversibly silence nociceptor input from the periphery, and control pain and hypersensitivity to mechanical stimuli.