Nociception

The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.

As a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8+ cold-sensing fibers express the heat-sensitive TRPV1 channel. Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8+ neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8+ cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8+ sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8+ cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.

BackgroundThe majority of postoperative patients report moderate to severe pain, possibly related to opioid underdosing or overdosing during surgery. Objective guidance of opioid dosing using the Nociception Level (NOL) index, a multiparameter artificial intelligence-driven index designed to monitor nociception during surgery, may lead to a more appropriate analgesic regimen, with effects beyond surgery. We tested whether NOL-guided opioid dosing during general anaesthesia results in less postoperative pain.MethodsIn this two-centre RCT, 50 patients undergoing abdominal surgery under fentanyl/sevoflurane anaesthesia were randomised to NOL-guided fentanyl dosing or standard care in which fentanyl dosing was based on haemodynamics. The primary endpoint of the study was postoperative pain assessed in the PACU.ResultsMedian postoperative pain scores were 3.2 (inter-quartile range 1.3-4.3) and 4.8 (3.0-5.3) in NOL-guided and standard care groups, respectively (P=0.006). Postoperative morphine consumption (standard deviation) was 0.06 (0.07) mg kg-1 (NOL-guided group) and 0.09 (0.09) mg kg-1 (control group; P=0.204). During surgery, fentanyl dosing was not different between groups (NOL-guided group: 6.4 [4.2] μg kg-1vs standard care: 6.0 [2.2] μg kg-1, P=0.749), although the variation between patients was greater in the NOL-guided group (% coefficient of variation 66% in the NOL-guided group vs 37% in the standard care group).ConclusionsDespite absence of differences in fentanyl and morphine consumption during and after surgery, a 1.6-point improvement in postoperative pain scores was observed in the NOL-guided group. We attribute this to NOL-driven rather than BP- and HR-driven fentanyl dosing during anaesthesia.Clinical trial registrationwww.trialregister.nl under identifier NL7845.

The gut microbiome has emerged as a promising target for modulating adverse effects of opioid exposure due to its significant role in health and disease. Opioid use disorder (OUD) has become increasingly prevalent, specifically in women of reproductive age, contributing to an increased incidence of offspring exposed to opioids in utero. Recent studies have shown that prenatal opioid exposure (POE) is associated with notable changes to the maternal gut microbiome, with subsequent implications for the offspring's microbiome and other adverse outcomes. However, the role of the gut microbiome in mediating sex-based differences in pain sensitivity has not yet been investigated. In this study, both male and female C57BL/6 offspring were used to determine sex-based differences in nociception and gut microbial composition as a result of POE. Our data reveals significant sex-based differences in offspring prenatally exposed to opioids. The gut microbiome of opioid-exposed females showed an enrichment of commensal bacteria including Lactobacillus compared to opioid-exposed males. Additionally, POE females demonstrated decreased nociceptive sensitivity, while males demonstrated increased nociceptive sensitivity. RNA sequencing of the prefrontal cortex showed sex-based differences in several canonical pathways, including an increase in the opioid signaling pathway of opioid-exposed females, which was not observed in males. Microbiome modification via maternal probiotic supplementation attenuated sex-based differences throughout the early stages of life. Together, our study provides further insight on sex-based differences arising from POE and highlights the pivotal role of the gut microbiome as a modifiable target for mitigating its negative effects.