Neurobiology of Pain, Interoception and Emotional Response: Lessons from Nerve Growth Factor-dependent Neurons

Although nerve growth factor (NGF) is a well-known neurotrophic factor, it also acts as a mediator of pain, itch and inflammation. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder caused by loss-of-function mutations in NTRK1, the gene encoding a receptor tyrosine kinase for NGF, TrkA. Mutations in NTRK1 cause the selective loss of NGF-dependent neurons in otherwise intact systems. NGF-dependent primary afferents are thinly myelinated Aδ or unmyelinated C-fibers that are dependent on the NGF-TrkA system during development. In CIPA, the lack of pain and the presence of anhidrosis (inability to sweat) are due to the absence of both NGF-dependent primary afferents and sympathetic postganglionic neurons, respectively. These peripheral neurons form an interface between the nervous system and the 'body-proper' and play essential roles in the interoception and sympathetic regulation of various tissues or organs. Patients with CIPA also show mental retardation and characteristic behaviors and are probably neuron-deficient within the brain. However, the functions of NGF-dependent neurons in the brain are controversial, both in animal and in human studies. This review focuses on various brain regions that express TrkA mRNA, based on data from the Allen Human Brain Atlas, and discusses putative neuronal networks related to these brain regions in humans. A better understanding the distribution of NGF-dependent neurons in the brain will provide a framework for further studies to investigate pain, interoception and emotional responses. Furthermore, strategies targeting the molecular mechanisms through which the NGF-TrkA system functions may provide hope for the development of novel analgesics.