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Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.

ABSTRACT: Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7-/-) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. We found that the nociceptive neurons of Nav1.7 knockout (Nav1.7-/-) mice, but not those of Nav1.8 knockout (Nav1.8-/-) mice, exhibited decreased pronociceptive serotonergic signaling through the 5-HT4 receptors, which are G?s-coupled GPCRs that stimulate the production of cyclic adenosine monophosphate resulting in protein kinase A (PKA) activity, as well as reduced abundance of the RII? regulatory subunit of PKA. Simultaneously, the efficacy of antinociceptive opioid signaling mediated by the G?i-coupled mu opioid receptors was increased. Consequently, opioids inhibited more efficiently tetrodotoxin-resistant sodium currents, which are important for pain-initiating neuronal activity in nociceptive neurons. Thus, Nav1.7 controls the efficacy and balance of GPCR-mediated pro- and antinociceptive intracellular signaling, such that without Nav1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia.

SUBMITTER: Isensee J

PROVIDER: S-EPMC6711404 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.

Isensee Jörg J Krahé Leonhardt L Moeller Katharina K Pereira Vanessa V Sexton Jane E JE Sun Xiaohui X Emery Edward E Wood John N JN Hucho Tim T

Science signaling 20170110 461

Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7-/-) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antin ...[more]

PMID: 28074005

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Project description: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.

Project description:Our previous studies have demonstrated that mice with reduced or absent serotonin transporter (SERT+/- and SERT-/- mice, respectively) are more sensitive to stress relative to their SERT normal littermates (SERT+/+ mice). The aim of the present study was to test the hypothesis that the hypothalamic-pituitary-adrenal (HPA) axis and its feedback regulation are impaired in these mice. The function and gene expression of several components in the HPA axis and its feedback regulation in SERT+/+, +/( and -/- mice were studied under basal (non-stressed) and stressed conditions. The results showed that (1) under basal conditions, corticotrophin-releasing factor (CRF) mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus was lower in both SERT+/( and (/( mice relative to SERT+/+ mice; (2) an increased response to CRF challenge was found in SERT(/( mice, suggesting that the function of CRF type 1 receptors (CRF R1) in the pituitary is increased. Consistent with these findings, (125)I-sauvagine (a CRF receptor antagonist) binding revealed an increased density of CRF R1 in the pituitary of SERT(/( under basal conditions. These data suggest that CRF R1 in the pituitary of SERT(/( mice is up-regulated. However, in the pituitary of SERT+/( mice, the function of CRF R1 was not changed and the density of CRF R1 was reduced relative to SERT+/+ mice; and (3) the expression of the glucocorticoid receptor (GR) in the hypothalamus, pituitary and adrenal cortex was significantly reduced in SERT+/( and (/( mice in comparison with SERT+/+ mice under basal conditions. Consistent with these findings, the corticosterone response to dexamethasone was blunted in SERT(/( mice relative to SERT+/+ and +/( mice. Furthermore, stress induces a rapid increase of the GR expression in the hypothalamus of SERT+/( and (/( mice relative to their basal levels. Together, the present results demonstrated that the HPA axis and its feedback regulation are altered in SERT knockout mice, which could account for the increased sensitivity to stress in these mice.

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Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.

Publications

Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.

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