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Background: Silent inflammatory bowel disease (IBD) is a condition in which individuals with the active disease experience minor to no pain. Voltage‐gated Na+ (NaV) channels expressed in sensory neurons play a major role in pain perception. Previously, we reported that a NaV1.8 genetic polymorphism (A1073V, rs6795970) was more common in a cohort of silent IBD patients. The expression of this variant (1073V) in rat sympathetic neurons activated at more depolarized potentials when compared to the more common variant (1073A). In this study, we investigated whether expression of either NaV1.8 variant in rat sensory neurons would exhibit different biophysical characteristics than previously observed in sympathetic neurons. Methods: Endogenous NaV1.8 channels were first silenced in DRG neurons and then either 1073A or 1073V human NaV1.8 cDNA constructs were transfected. NaV1.8 currents were recorded with the whole‐cell patch‐clamp technique. Key Results: The results indicate that 1073A and 1073V NaV1.8 channels exhibited similar activation values. However, the slope factor (k) for activation determined for this same group of neurons decreased by 5 mV, suggesting an increase in voltage sensitivity. Comparison of inactivation parameters indicated that 1073V channels were shifted to more depolarized potentials than 1073A‐expressing neurons, imparting a proexcitatory characteristic. Conclusions and Inferences: These findings differ from previous observations in other expression models and underscore the challenges with heterologous expression systems. Therefore, the use of human sensory neurons derived from induced pluripotent stem cells may help address these inconsistencies and better determine the effect of the polymorphism present in IBD patients. [ABSTRACT FROM AUTHOR]

The nodose ganglion (NG) is the main parasympathetic ganglion conveying sensory signals to the CNS from numerous visceral organs including digestive signals such as gastric distension or the release the gastrointestinal peptides. The response characteristics of NG neurons to ATP and ADP and pharmacological interrogation of purinergic receptor subtypes have been previously investigated but often in NG cells of undetermined visceral origin. In this study, we confirmed the presence of P2X3 and P2Y1 receptors and characterized P2X and P2Y responses in gastric-innervating NG neurons. Application of ATP-evoked large inward currents and cytosolic Ca2+ increases in gastric-innervating NG neurons. Despite the expression of P2Y1 receptors, ADP elicited only minor modulation of voltage-gated Ca2+ channels. Considering the sensitivity of NG neurons to comorbidities associated with disease or neural injury, purinergic modulation of gastric NG neurons in disease- or injury-states is worthy of further investigation. [ABSTRACT FROM AUTHOR]

Several studies have shown that human carriers of the single nucleotide polymorphism of the μ-opioid receptor, OPRM1 A118G, exhibit greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present study, we employed a ‘humanized’ mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in our model of drug-induced suppression of a natural reward cue and to compare the morphine pharmacological profile in acutely isolated sensory neurons. Compared with 118AA mice, our results demonstrate that homozygous 118GG mice exhibit greater avoidance of the cocaine-paired saccharin cue, a behavior linked to an aversive withdrawal-like state. Electrophysiological recordings confirmed the reduced modulation of Ca 2 + channels by morphine in trigeminal ganglion (TG) neurons from 118GG mice compared to the 118AA control cells. However, repeated cocaine exposure in 118GG mice led to a leftward shift of the morphine concentration–response relationship when compared with 118GG control mice, while a rightward shift was observed in 118AA mice. These results suggest that cocaine exposure of mice carrying the 118G allele leads to a heightened sensitivity of the reward system and a blunted modulation of Ca 2 + channels by morphine in sensory neurons. [ABSTRACT FROM AUTHOR]

The exercise pressor reflex, a crucial component of the cardiovascular response under physiological and pathophysiological states, is activated via metabolic and mechanical mediators that originate from contracting muscles and stimulate group III and IV afferents. We reported previously that stimulation of mu opioid receptors (MOR), expressed in both afferents, led to a significant attenuation of the reflex in rats whose femoral arteries had been occluded for 72 h. The present study examined the effect of arterial occlusion on the signaling components involved in the opioid-mediated modulation of Ca2+ channels in rat dorsal root ganglion neurons innervating the triceps surae muscles. We focused on neurons that were transfected with cDNA coding for enhanced green fluorescent protein whose expression is driven by the voltagegated Na+ channel 1.8 (NaV1.8) promoter region, a channel expressed primarily in nociceptive neurons. With the use of a small interference RNA approach, our results show that the pertussis toxin-sensitive Gαi3 subunit couples MOR with Ca2+ channels. We observed a significant leftward shift of the MOR agonist [D-Ala2-N-Me-Phe4- Glycol5]-enkephalin concentration-response relationship in neurons isolated from rats with occluded arteries compared with those that were perfused freely. Femoral occlusion did not affect Ca2+ channel density or the fraction of the main Ca2+ channel subtype. Furthermore, Western blotting analysis indicated that the leftward shift did not result from either increased Gαi3 or MOR expression. Finally, all neurons from both groups exhibited an inward current following exposure of the transient potential receptor vanilloid 1 (TRPV1) agonist, 8-methyl-N-vanillyl-6-nonenamide. These findings suggest that sensory neurons mediating the exercise pressor reflex express NaV1.8 and TRPV1 channels, and femoral occlusion alters the MOR pharmacological profile. [ABSTRACT FROM AUTHOR]