Women suffer chronic pain more frequently than men. It is not clear whether this is due to differences in higher level cognitive processes or basic nociceptive responses. In this study we used a mouse model of neuropathic pain to dissociate these factors. We performed RNA-seq on purified peripheral afferent neurons, but found no striking differences in gene expression between male and female mice, neither before nor after nerve injury. Similarly, spinal cord immune responses between the sexes appeared to be indistinguishable when studied by flow cytometry or qRT-PCR. Differences emerged only upon studying peripheral immune cell infiltration into the dorsal root ganglion, suggesting that adaptive immune responses in neuropathic pain could be sexually dimorphic.

Voltage-gated sodium channel Na 1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of Na 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific Na 1.7 knockout mouse (Na 1.7 ) and selective small-molecule Na 1.7 antagonist PF-5198007. Na 1.7 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both Na 1.7 and littermate controls. Loss, or blockade, of Na 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of Na 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed Na 1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of Na 1.7 (in Na 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective Na 1.7 antagonist PF-5198007. Our data demonstrate that Na 1.7 (in Na 1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of Na 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.

We explored the effects of baroreceptor afferents laterality and sexual dimorphism on the expression of cardiovascular reflex responses to baroreflex activation in Sprague Dawley (SD) rats. Under urethane anesthesia, rats of either sex (total n = 18) were instrumented for left, right and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR) and mesenteric (MVR) and femoral (FVR) vascular resistance. Female rats were matched for the diestrus phase of the estrus cycle. Left, right and bilateral ADN stimulation evoked frequency-dependent drops in MAP, HR, and MVR, and increases in FVR. Irrespective of sex, left and bilateral ADN stimulation as compared to right-sided stimulation mediated greater reflex reductions in MAP, HR, and MVR but not in FVR. In males, reflex bradycardic responses were greater in response to bilateral stimulation relative to both left-and right-sided stimulation. In females, left ADN stimulation evoked the largest increase in FVR. Left and bilateral ADN stimulations evoked greater reductions in MAP and MVR while left-sided stimulation produced larger increases in FVR in females compared with males. All other reflex responses to ADN stimulation were relatively comparable between males and females. These results show a differential baroreflex processing of afferent neurotransmission promoted by left versus right baroreceptor afferent inputs and sexual dimorphism in the expression of baroreflex responses in rats of either sex. Collectively, these data add to our understanding of physiological mechanisms pertaining to baroreflex control in both males and females.

Objective: Neuromodulation of blood pressure using baroreflex activation therapy is an effective means to control hypertension in resistant hypertensive patients. In a genetic rat model of essential hypertension, the spontaneously hypertensive rats (SHRs); we were able to demonstrate in male rats that preferential central integration of left baroreceptor afferent input exists relative to that of the right afferents. It remains unknown whether laterality also influences baroreflex responses in female SHRs. Accordingly, the differences in cardiovascular responses triggered by stimulation of the left and right baroreceptor afferents, as assessed by direct electrical stimulation of the aortic depressor nerve (ADN), were studied in female SHRs. Design and method: Pentobarbital-anesthetized female SHRs (25–29 weeks, n = 6–8) were instrumented for left and right ADN stimulation (1–40 Hz, 0.2 ms, 0.4 mA for 20 s) and recording of mean arterial pressure (MAP), heart rate (HR) and mesenteric (MVR) and femoral (FVR) vascular resistance. Female rats were also matched for the diestrus phase of the estrus cycle. Results: Both left and right ADN stimulation resulted in frequency-dependent reductions (P < 0.001) in MAP, HR, MVR and FVR. Reflex reductions in MAP, HR, MVR and FVR were comparable for both left-sided and right-sided stimulation. Conclusions: Unlike males, female SHRs express no differential central modulation of baroreceptor afferent input as evidenced by the comparable left versus right baroreflex-mediated depressor responses. Similar depressor responses in the left versus right stimulation may have been contributed to by the lack of differences in baroreflex-driven changes in HR and vascular resistance. Clinically, targeting either the left or right aortic nerves may equally provide adequate reductions in blood pressure in female hypertensive subjects. Future studies should elucidate the mechanisms responsible for sex differences in the central processing of baroreflex between male and female SHRs.

In this article, we describe the discovery of an aryl ether series of potent and selective Na1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Na channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Na1.3 as a target for pain.