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.

[Nerve growth factor and the physiology of pain: the relationships among interoception, sympathetic neurons and the emotional response indicated by the molecular pathophysiology of congenital insensitivity to pain with anhidrosis].

Nerve growth factor (NGF) is a neurotrophic factor essential for the survival and maintenance of neurons. Congenital insensitivity to pain with anhidrosis (CIPA) is caused by loss-of-function mutations in NTRK1, which encodes a receptor tyrosine kinase, TrkA, for NGF. Mutations in NTRK1 cause the selective loss of NGF-dependent neurons, including both NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. The NGF-dependent primary afferents are thinly myelinated AΔ or unmyelinated C-fibers that are dependent on the NGF-TrkA system during development. NGF-dependent primary afferents are not only nociceptive neurons that transmit pain and temperature sensation, but also are polymodal receptors that play essential roles for interoception by monitoring various changes in the physiological status of all tissues in the body. In addition, they contribute to various inflammatory processes in acute, chronic and allergic inflammation. Together with sympathetic postganglionic neurons, they maintain the homeostasis of the body and emotional responses via interactions with the brain, immune and endocrine systems. Pain is closely related to emotions that accompany physical responses induced by systemic activation of the sympathetic nervous system. In contrast to a negative image of emotions in daily life, Antonio Damasio proposed the 'Somatic Marker Hypothesis', wherein emotions play critical roles in the decision-making and reasoning processes. According to this hypothesis, reciprocal communication between the brain and the body-proper are essential for emotional responses. Using the pathophysiology of CIPA as a foundation, this article suggests that NGF-dependent neurons constitute a part of the neuronal network required for homeostasis and emotional responses, and indicates that this network plays important roles in mediating the reciprocal communication between the brain and the body-proper.

Chronic thromboembolic pulmonary hypertension complicated with homocystinuria.

A 17-year-old boy with homocystinuria was found to have a systolic murmur during a routine examination. Echocardiography demonstrated pulmonary hypertension (PH), and computer tomography angiography showed pulmonary thrombi. Although 12-month anticoagulation treatment reduced the thrombotic material within the main branch, it failed to clear thrombotic materials in the left and right lobar branches. Two years later, the patient was admitted to our hospital due to a worsening of PH. Treatment with bosentan, sildenafil and beraprost, in addition to anti-coagulant therapy, did not improve his PH. Balloon pulmonary angioplasty (BPA) was performed to remove the pulmonary thrombi. BPA markedly improved the patient's hemodynamics and exercise capacity. Close follow-up is scheduled to prevent any potential future thrombotic complications.

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.

Nerve growth factor, pain, itch and inflammation: lessons from congenital insensitivity to pain with anhidrosis.

NGF is a well-known neurotrophic factor essential for the survival and maintenance of primary afferent neurons and sympathetic neurons. NGF is also an inflammatory mediator associated with pain and itch. Congenital insensitivity to pain with anhidrosis is a genetic disorder due to loss-of-function mutations in the NTRK1 gene encoding TrkA, a receptor tyrosine kinase for NGF. Since patients with congenital insensitivity to pain with anhidrosis lack NGF-dependent unmyelinated (C-) and thinly myelinated (Aδ-) fibers, and their dermal sweat glands are without innervation, they exhibit no pain, itch, signs of neurogenic inflammation or sympathetic skin responses. Based on the pathophysiology of congenital insensitivity to pain with anhidrosis, this article indicates how NGF-dependent neurons are essential for the establishment of neural networks for interoception and homeostasis, and play crucial roles in brain-immune-endocrine interactions in pain, itch and inflammation. In addition, it refers to involvements of the NGF-TrkA system in various disease states, and potential pharmacological effects when this system is targeted.

Nerve growth factor, interoception, and sympathetic neuron: lesson from congenital insensitivity to pain with anhidrosis.

Nerve growth factor (NGF) is a well-known neurotrophic factor essential for the survival and maintenance of sensory and sympathetic neurons. Congenital insensitivity to pain with anhidrosis (CIPA) is a genetic disorder due to loss-of-function mutations in the NTRK1 (also known as TRKA) gene encoding TrkA, a receptor tyrosine kinase for NGF. Patients with CIPA provide us a rare opportunity to explore the developmental and physiological function of the NGF-dependent neurons in behavior, cognitive, and mental activities that are not available in animal studies. Here, I discuss the significance of findings that patients with CIPA lack NGF-dependent neurons, including interoceptive polymodal receptors, sympathetic postganglionic neurons, and probably several types of neurons in the brain. They also exhibit characteristic emotional behavior or problems. Together, the NGF-TrkA system is essential for the establishment of a neural network for interoception and homeostasis that may underlie 'gut feelings'. Thus, NGF-dependent neurons play a crucial role in emotional experiences and decision-making processes. Prospective studies focused on these neurons might provide further insights into the neural basis of human emotion and feeling.

No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V.

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal recessive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neurophysiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKA gene, encoding a receptor tyrosine kinase for nerve growth factor and responsible for HSAN-IV, but we could not detect any mutation. These data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients.

Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor.

Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is an autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis (inability to sweat), absence of reaction to noxious (or painful) stimuli, self-mutilating behavior and mental retardation. The anomalous pain and temperature sensation and anhidrosis in CIPA are due to the absence of afferent neurons activated by tissue-damaging stimuli and a loss of innervation of eccrine sweat glands, respectively. Nerve growth factor (NGF) supports the survival of nociceptive sensory and autonomic sympathetic neurons as well as cholinergic neurons of the basal forebrain. The human TRKA (NTRKI) gene located on chromosome 1 (1q21-q22) encodes a receptor tyrosine kinase (RTK) which is autophosphorylated in response to NGF, thus, activating various pathways of intracellular signal transduction. We earlier identified the genetic basis of CIPA by detecting mutations in TRKA gene of patients. Defects in NGF signal transduction at its receptor lead to failure to survive as various NGF dependent neurons are not maintained, most probably due to apoptosis during development. TRKA mutations are distributed in an extracellular domain involved in NGF binding, as well as in the intracellular signal-transduction domain. Missense mutations with loss of function provide considerable insight into the structure-function relationship in the RTK family. In view of the fact that defects in TRKA cause CIPA, the molecular pathology of CIPA provides unique opportunities to explore critical roles of the NGF-TRKA receptor system. Thus, CIPA can serve as a useful model to determine mechanisms of development and maintenance of NGF-dependent neurons in autonomic, sensory and central nervous systems, as well as the physiology of these neurons in humans.