scholarly journals The Perception and Endogenous Modulation of Pain

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-25 ◽  
Author(s):  
Michael H. Ossipov
Keyword(s):  
Pain Perception ◽  
Survival Function ◽  
Pain Matrix ◽  
Voltage Gated Sodium Channels ◽  
Congenital Insensitivity ◽  
Trka Receptors ◽  
Genomic Studies ◽  
Congenital Insensitivity To Pain ◽  
Subcortical Regions ◽  
As Stress

Pain is often perceived an unpleasant experience that includes sensory and emotional/motivational responses. Accordingly, pain serves as a powerful teaching signal enabling an organism to avoid injury, and is critical to survival. However, maladaptive pain, such as neuropathic or idiopathic pain, serves no survival function. Genomic studies of individuals with congenital insensitivity to pain or paroxysmal pain syndromes considerable increased our understanding of the function of peripheral nociceptors, and especially of the roles of voltage-gated sodium channels and of nerve growth factor (NGF)/TrkA receptors in nociceptive transduction and transmission. Brain imaging studies revealed a “pain matrix,” consisting of cortical and subcortical regions that respond to noxious inputs and can positively or negatively modulate pain through activation of descending pain modulatory systems. Projections from the periaqueductal grey (PAG) and the rostroventromedial medulla (RVM) to the trigeminal and spinal dorsal horns can inhibit or promote further nociceptive inputs. The “pain matrix” can explain such varied phenomena as stress-induced analgesia, placebo effect and the role of expectation on pain perception. Disruptions in these systems may account for the existence idiopathic pan states such as fibromyalgia. Increased understanding of pain modulatory systems will lead to development of more effective therapeutics for chronic pain.

scholarly journals Genomic, Ancestral and Networking Analyses of a High-Altitude Native American Ecuadorian Patient with Congenital Insensitivity to Pain with Anhidrosis

2019 ◽  
Author(s):  
Andrés López-Cortés ◽  
Ana Karina Zambrano ◽  
Patricia Guevara-Ramírez ◽  
Byron Albuja Echeverría ◽  
Santiago Guerrero ◽  
...  
Keyword(s):  
Native American ◽  
High Altitude ◽  
African Ancestry ◽  
Genomic Analysis ◽  
European Ancestry ◽  
Tyrosine Kinase Receptor ◽  
Pain Matrix ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

ABSTRACTCongenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Patients with CIPA lack the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we conducted a genomic analysis of 4,811 genes and 18,933 variants, including 54 mutations of NTRK1 in a high-altitude indigenous Ecuadorian patient with CIPA. As results, the patient presented 87.8% of Native American ancestry, 6.6% of African ancestry and 5.6% of European ancestry. The mutational analysis of the kinase domain of NTRK1 showed two pathogenic mutations, rs80356677 (Asp674Tyr) and rs763758904 (Arg602*). The genomic analysis showed 68 pathogenic and/or likely pathogenic variants in 45 genes, and two variants of uncertain significance in CACNA2D1 (rs370103843) and TRPC4 (rs80164537) genes involved in the pain matrix. The GO enrichment analysis showed 28 genes with relevant mutations involved in several biological processes, cellular components and molecular functions. In addition, the protein-protein interaction (PPi) networking analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix. In conclusion, this is the first time that a study associates genomic, ancestral and networking data in a high-altitude Native American Ecuadorian patient with consanguinity background in order to better understand CIPA pathogenesis.

scholarly journals Understanding the genetic basis of congenital insensitivity to pain

2020 ◽  
Vol 133 (1) ◽  
pp. 65-78 ◽  
Author(s):  
Ichrak Drissi ◽  
William Aidan Woods ◽  
Christopher Geoffrey Woods
Keyword(s):  
Genetic Basis ◽  
Genetic Disorders ◽  
Endogenous Opioids ◽  
Journal Articles ◽  
Intracellular Signalling Pathways ◽  
Voltage Gated Sodium Channels ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain ◽  
Increased Susceptibility

Abstract Introduction or background Congenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders. CIP individuals demonstrate the unexpectedly severe consequences of painlessness. Although only a small number of causative conditions and genes are known, most have led to profound insights into human nociception. CIP gene discovery is catalyzing the manufacture of completely new classes of analgesics, and these are needed as alternatives to synthetic highly potent opioids. Sources of data Pubmed.gov peer-reviewed journal articles and reviews. Areas of agreement The importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing. New analgesics can be generated from knowledge of the NGF-TRKA nociceptor pathway. Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling. Mutations in the voltage-gated sodium channels SCN9A and SCN11A can cause congenital painlessness, and in contradistinction, other mutations can cause episodic neuropathic pain. SCN9A/Nav1.7 is an analgesic target. SCN11A/Nav1.9 is unlikely to be an analgesic target. There are further Mendelian causes of painlessness to be discovered. Areas of controversy Which NGF-TRKA intracellular signalling pathways operate in nociceptor development and which in post-natal pain sensing? Why have no clinically effective Nav1.7 antagonist been generated? SCN9A-CIP causes analgesia, at least in part, through endogenous opioids. Why do all CIP phenotypes involve a complete loss of all types of nociception? Areas timely for developing research PRDM12 as an analgesic target. Discovery of the function and analgesic potential of new CIP genes. Can NGF-TRKA be used in the treatment of S. aureus?

scholarly journals Guided growth in the correction of knee deformity in patients with congenital insensitivity to pain

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Soroush Baghdadi ◽  
Sadegh Saberi ◽  
Taghi Baghdadi
Keyword(s):  
Demographic Data ◽  
Joint Destruction ◽  
Walking Ability ◽  
Guided Growth ◽  
Tertiary Referral Hospital ◽  
Common Procedure ◽  
Correction Rate ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Abstract Background Orthopedic manifestations of congenital insensitivity to pain (CIP) can be devastating if left untreated. Knee deformities are common in patients with CIP and might lead to joint destruction and loss of walking ability. The purpose of the present study was to report the results and complications of guided growth procedures around the knee in patients with CIP. Methods In a retrospective review, all patients with CIP who underwent guided growth procedures around the knee from 2009 to 2017 at a tertiary referral hospital were evaluated. Patients with secondary insensitivity to pain (e.g., syringomyelia), as well as patients with incomplete records, were excluded. Demographic data, clinical findings, correction rate, and complications were recorded. Results Ten knees in six patients fulfilled the inclusion criteria. The median age was 10 (range, 5–12), with a mean follow-up of 31 months (range, 16–56). Distal femoral tension-band hemiepiphysiodesis was the most common procedure, followed by proximal tibial hemiepiphysiodesis. The mean correction rate was 0.28°/month for femoral deformity. Staples were removed prematurely in one patient due to extrusion. No cases of infection or skin dehiscence were observed. None of the patients needed a reconstructive knee procedure during the study period. Conclusions The findings of this study suggest that guided growth procedures might have a role in the correction of knee deformities in patients with CIP. However, the correction rate is lower than that of typically developing children, patients should be closely followed to prevent complications, and stringent patient selection criteria should be followed to ensure success.

scholarly journals Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis

2017 ◽  
Vol 45 (2) ◽  
pp. 549-555 ◽  
Author(s):  
Ting Wang ◽  
Haibo Li ◽  
Jingjing Xiang ◽  
Bin Wei ◽  
Qin Zhang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Nonsense Mutation ◽  
Mutation Screening ◽  
Receptor Type ◽  
Tyrosine Kinase Receptor ◽  
Site Mutation ◽  
Congenital Insensitivity ◽  
Congenital Insensitivity To Pain ◽  
Insensitivity To Pain

Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron–exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851-33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA.

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