Description:
<jats:title>Abstract</jats:title><jats:p>Nerve growth factor (<jats:styled-content style="fixed-case">NGF</jats:styled-content>) signaling is important in the development and functional maintenance of nociceptors, but it also plays a central role in initiating and sustaining heat and mechanical hyperalgesia following inflammation. <jats:styled-content style="fixed-case">NGF</jats:styled-content> signaling in pain has traditionally been thought of as primarily engaging the classic high‐affinity receptor tyrosine kinase receptor TrkA to initiate sensitization events. However, the discovery that secreted proforms of nerve <jats:styled-content style="fixed-case">NGF</jats:styled-content> have biological functions distinct from the processed mature factors raised the possibility that these proneurotrophins (pro<jats:styled-content style="fixed-case">NT</jats:styled-content>s) may have distinct function in painful conditions. Pro<jats:styled-content style="fixed-case">NT</jats:styled-content>s engage a novel receptor system that is distinct from that of mature neurotrophins, consisting of sortilin, a type I membrane protein belonging to the <jats:styled-content style="fixed-case">VPS</jats:styled-content>10p family, and its co‐receptor, the classic low‐affinity neurotrophin receptor p75<jats:styled-content style="fixed-case">NTR</jats:styled-content>. Here, we review how this new receptor system may itself function with or independently of the classic TrkA system in regulating inflammatory or neuropathic pain.</jats:p>