Pharmacological characterization of a rat Nav1.7 loss-of-function model with insensitivity to pain.

Sodium channel Nav1.7, encoded by the SCN9A gene, is a well-validated target that plays a key role in controlling pain sensation. Loss-of-function mutations of Nav1.7 can cause a syndrome of profound congenital insensitivity to pain in humans. Better understanding of how the loss of Nav1.7 leads to loss of pain sensibility would help to decipher the fundamental mechanisms of nociception and inform strategies for development of novel analgesics. Using a recently described rat Nav1.7 loss-of-function model with deficient nociception but intact olfactory function, we investigated the involvement of endogenous opioid and cannabinoid systems in this rodent model of Nav1.7-related congenital insensitivity to pain. We found that both the opioid receptor antagonist naloxone and cannabinoid receptor blockers SR141716A (rimonabant) and SR144528 fail to restore acute pain sensitivity in Nav1.7 loss-of-function rats. We observed, however, that after rimonabant administration, Nav1.7 loss-of-function but not WT rats displayed abnormal behaviours, such as enhanced scratching, caudal self-biting, and altered facial expressions; the underlying mechanism is still unclear. Dorsal root ganglion neurons from Nav1.7 loss-of-function rats, although hypoexcitable compared with WT neurons, were still able to generate action potentials in response to noxious heat and capsaicin. Our data indicate that complete loss of dorsal root ganglion neuron excitability is not required for insensitivity to pain and suggest that endogenous opioid and cannabinoid systems are not required for insensitivity to pain in the absence of Nav1.7 channels in this rat Nav1.7 loss-of-function model.

Insensitivity to Pain upon Adult-Onset Deletion of Nav1.7 or Its Blockade with Selective Inhibitors.

Strong human genetic evidence points to an essential contribution of the voltage-gated sodium channel Nav1.7 to pain sensation: loss of Nav1.7 function leads to congenital insensitivity to pain, whereas gain-of-function mutations in the SCN9A gene that encodes Nav1.7 cause painful neuropathies, such as inherited erythromelalgia, a syndrome characterized by episodic spontaneous pain. Selective Nav1.7 channel blockers thus hold promise as potential painkillers with improved safety and reduced unwanted side effects compared with existing therapeutics. To determine the maximum effect of a theoretically perfectly selective Nav1.7 inhibitor, we generated a tamoxifen-inducible KO mouse model enabling genetic deletion of Nav1.7 from adult mice. Electrophysiological recordings of sensory neurons from these mice following tamoxifen injection demonstrated the loss of Nav1.7 channel current and the resulting decrease in neuronal excitability of small-diameter neurons. We found that behavioral responses to most, but surprisingly not all, modalities of noxious stimulus are abolished following adult deletion of Nav1.7, pointing toward indications where Nav1.7 blockade should be efficacious. Furthermore, we demonstrate that isoform-selective acylsulfonamide Nav1.7 inhibitors show robust analgesic and antinociceptive activity acutely after a single dose in mouse pain models shown to be Nav1.7-dependent. All experiments were done with both male and female mice. Collectively, these data expand the depth of knowledge surrounding Nav1.7 biology as it relates to pain, and provide preclinical proof of efficacy that lays a clear path toward translation for the therapeutic use of Nav1.7-selective inhibitors in humans.SIGNIFICANCE STATEMENT Loss-of-function mutations in the sodium channel Nav1.7 cause congenital insensitivity to pain in humans, making Nav1.7 a top target for novel pain drugs. Targeting Nav1.7 selectively has been challenging, however, in part due to uncertainties in which rodent pain models are dependent on Nav1.7. We have developed and characterized an adult-onset Nav1.7 KO mouse model that allows us to determine the expected effects of a theoretically perfect Nav1.7 blocker. Importantly, many commonly used pain models, such as mechanical allodynia after nerve injury, appear to not be dependent on Nav1.7 in the adult. By defining which models are Nav1.7 dependent, we demonstrate that selective Nav1.7 inhibitors can approximate the effects of genetic loss of function, which previously has not been directly established.

Congenital insensitivity to pain and anhidrosis: Case report and review of findings along neuro-immune axis in the disorder.

Congenital insensitivity to pain and anhidrosis (CIPA) is one of the hereditary autonomic and sensory neuropathies. Typically presenting in infancy, it manifests as hyperpyrexia from defects in sweating (autonomic) and self-mutilating injuries from pain insensitivity (sensory). CIPA being rare in North America, diagnosis is often missed due to variable presentation. Subsequent management of its complications is therefore delayed. We report an unusual presentation in a 2-year-old girl with preexisting diagnosis of CIPA who was evaluated for bilateral upper extremity paresis of insidious onset. MRI revealed a mass compressing her cervical spine as the cause, and work up suggested immune dysfunction as possible etiology. To our knowledge, this complication has not been reported before in association with the disease. We introduce the disease by explaining the molecular pathology behind its presenting features. The neurological findings, documented in association with CIPA, are summarized and serve as a reference for the various presentations of this rare disorder. Since this disease is known to affect the immune system, immune defects in CIPA are discussed with recommendations for surveillance of patient's immune status.

Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.

We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage-dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.

Sodium channelopathies and pain.

Chronic pain often represents a severe, debilitating condition. Up to 10% of the worldwide population are affected, and many patients are poorly responsive to current treatment strategies. Nociceptors detect noxious conditions to produce the sensation of pain, and this signal is conveyed to the CNS by means of action potentials. The fast upstroke of action potentials is mediated by voltage-gated sodium channels, of which nine pore-forming alpha-subunits (Nav1.1-1.9) have been identified. Heterogeneous functional properties and distinct expression patterns denote specialized functions of each subunit. The Nav1.7 and Nav1.8 subunits have emerged as key molecules involved in peripheral pain processing and in the development of an increased pain sensitivity associated with inflammation and tissue injury. Several mutations in the SCN9A gene encoding for Nav1.7 have been identified as important cellular substrates for different heritable pain syndromes. This review aims to cover recent progress on our understanding of how biophysical properties of mutant Nav1.7 translate into an aberrant electrogenesis of nociceptors. We also recapitulate the role of Nav1.8 for peripheral pain processing and of additional sodium channelopathies which have been linked to disorders with pain as a significant component.

Effect of naloxone in a previously undescribed hypothalamic syndrome. A disorder of the endogenous opioid peptide system?

A syndrome of disordered hypothalamic function with abnormal control of temperature, appetite, and thirst, hyperprolactinaemia, and inappropriate vasopressin release is described in a 13-year-old boy who, in addition, had insensitivity to pain and a more general disorder affecting mood, sleep, and control of respiration. A disturbance of the opioid peptide system is postulated. Naloxone reversed central analgesia, altered urine fluid and electrolyte excretion, modified the hormonal response to gonadotrophin-releasing and thyrotrophin-releasing hormones, and improved the auditory and visual reaction times. Specific opioid antagonists may have a therapeutic role.

[Endorphins--endogenous peptides with morphine-like effects. 2. Biological importance, clinical apsects]. / Endorphine--körpereigene Peptide mit Morphin-ähnlicher Wirkung. Teil 2: Biologische Bedeutung, klinische Gesichtspunkte.

Since 1974 peptides with opiate-like action both in vivo and in vitro have been isolated from the nervous system of various vertebrates and man. The localization of these peptides (endorphins) within the central and peripheral nervous system reflects the possible biological functions in which they may participate: the response of the CNS to painful stimuli (dorsal horn of the spinal cord, central grey matter, thalamus); the control of emotions (limbic system); the regulation of vegetative functions (medulla oblongata); the response of the body to stress the control of endocrine function (hypothalamus, infundibulum, hypophysis); the control of extrapyramidal motor activity (brain stem) or the control of intestinal motility (intramural nervous plexus). Up-to-date knowledge suggests that the endorphins may function as neurotransmitters, neuromodulators or hormones and that such functions vary according to the special sites of synthesis, storage and action of these various peptides within the body.