NGF-dependent neurons and neurobiology of emotions and feelings: Lessons from congenital insensitivity to pain with anhidrosis.

NGF is a well-studied neurotrophic factor, and TrkA is a receptor tyrosine kinase for NGF. The NGF-TrkA system supports the survival and maintenance of NGF-dependent neurons during development. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder due to loss-of-function mutations in the NTRK1 gene encoding TrkA. Individuals with CIPA lack NGF-dependent neurons, including NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. Thus, the pathophysiology of CIPA can provide intriguing findings to elucidate the unique functions that NGF-dependent neurons serve in humans, which might be difficult to evaluate in animal studies. Preceding studies have shown that the NGF-TrkA system plays critical roles in pain, itching and inflammation. This review focuses on the clinical and neurobiological aspects of CIPA and explains that NGF-dependent neurons in the peripheral nervous system play pivotal roles in interoception and homeostasis of our body, as well as in the stress response. Furthermore, these NGF-dependent neurons are likely requisite for neurobiological processes of 'emotions and feelings' in our species.

[Congenital insensitivity to pain]. / L'insensibilité congénitale à la douleur.

Congenital insensitivity to pain (CIP) is a rare syndrome with various clinical expressions, characterized by a dramatic impairment of pain perception since birth. In the 1980s, progress in nerve histopathology allowed to demonstrate that CIP was almost always a manifestation of hereditary sensory and autonomic neuropathies (HSAN) involving the small-calibre (A-delta and C) nerve fibres which normally transmit nociceptive inputs along sensory nerves. Identification of the genetic basis of several clinical subtypes has led to a better understanding of the mechanisms involved, emphasizing in particular the crucial role of nerve growth factor (NGF) in the development and survival of nociceptors. Recently, mutations of the gene coding for the sodium channel Nav1.7--a voltage-dependent sodium channel expressed preferentially on peripheral nociceptors and sympathetic ganglia--have been found to be the cause of CIP in patients showing a normal nerve biopsy. This radical impairment of nociception mirrors the hereditary pain syndromes associated with "gain of function" mutations of the same ion channel, such as familial erythromelalgia and paroxysmal extreme pain disorder. Future research with CIP patients may identify other proteins specifically involved in nociception, which might represent potential targets for chronic pain treatment. Moreover, this rare clinical syndrome offers the opportunity to address interesting neuropsychological issues, such as the role of pain experience in the construction of body image and in the empathic representation of others' pain.

Dominantly transmitted congenital indifference to pain.

Two patients from a family with dominantly inherited indifference to pain were investigated. Perception of the other sensory modalities was normal as was the remainder of the neurological examination. Electrophysiological studies and morphometric evaluation of myelinated and unmyelinated fibers of nerve biopsy specimens were normal. This is the first morphometric study of peripheral nerve in dominantly inherited indifference to pain.