The transient receptor potential ion channel TRPA1 is a Ca2+-permeable nonselective cation channel widely expressed in sensory neurons, but also in many nonneuronal tissues typically possessing barrier functions, such as the skin, joint synoviocytes, cornea, and the respiratory and intestinal tracts. Here, the primary role of TRPA1 is to detect potential danger stimuli that may threaten the tissue homeostasis and the health of the organism. The ability to directly recognize signals of different modalities, including chemical irritants, extreme temperatures, or osmotic changes resides in the characteristic properties of the ion channel protein complex. Recent advances in cryo-electron microscopy have provided an important framework for understanding the molecular basis of TRPA1 function and have suggested novel directions in the search for its pharmacological regulation. This chapter summarizes the current knowledge of human TRPA1 from a structural and functional perspective and discusses the complex allosteric mechanisms of activation and modulation that play important roles under physiological or pathophysiological conditions. In this context, major challenges for future research on TRPA1 are outlined.

OBJECTIVE: Pharmacologic pain treatments lack specific targeting and often produce unwanted side effects (eg, addiction, additional hyperalgesia). We previously established that the direct application of laser irradiation (direct photobiomodulation [PBM]) of the sural nerve reduces thermal hypersensitivity in a rodent model of chronic pain, but not mechanical hypersensitivity. These observations were consistent with a selective reduction in the small-diameter fiber contribution to electrophysiologically measured evoked response after direct PBM of a sensory nerve (saphenous). However, to our knowledge, direct application of laser irradiation has never been performed in an animal model of acute nociceptive pain or on a mixed nerve in which sensory and motor outcomes can be observed.
METHODS: In this study, we describe the effects of direct application of laser irradiation (808 nm, 60 mW, 4 minutes) on a mixed nerve (sciatic nerve) in an acute nociceptive pain model (intradermal capsaicin injection) in rats over the course of two weeks. To investigate whether laser irradiation of a mixed nerve alters motor function, in separate experiments, we applied laser irradiation to the sciatic nerve (using the same parameters as in the chronic pain experiments), and force generation of the gastrocnemius was measured.
RESULTS: Capsaicin-induced hypersensitivities to mechanical (pin prick) and thermal (Hargreaves) noxious stimuli, associated with Aδ- and C-fibers, showed a maximal reduction of 70% and 56.2%, respectively, by direct PBM, when compared with a control group (vehicle injection, no PBM) on the same day. This reduction was determined to be significant using a mixed-design analysis of variance with a p value < 0.05. Force generation remained unchanged for up to 120 minutes after laser irradiation. In summary, direct PBM selectively inhibits C- and Aδ-fiber transmission while leaving Aɑ-, Aβ-, and motor-fiber activity intact.
CONCLUSIONS: These results, in conjunction with our previous analyses of laser irradiation effects on the sural nerve in a chronic spared nerve injury pain model, suggest that direct PBM is a promising candidate for treating pain induced by small-diameter fiber activity.

Sleep disturbances and persistent pain conditions are public health challenges worldwide. Although it is well-known that sleep deficit increases pain sensitivity, the underlying mechanisms remain elusive. We have recently demonstrated the involvement of nucleus accumbens (NAc) and anterior cingulate cortex (ACC) in the pronociceptive effect of sleep restriction. In this study, we found that sleep restriction increases c-Fos expression in NAc and ACC, suggesting hyperactivation of these regions during prolonged wakefulness in male Wistar rats. Blocking adenosine A2A receptors in the NAc or GABAA receptors in the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), or locus coeruleus (LC) effectively mitigated the pronociceptive effect of sleep restriction. In contrast, the blockade of GABAA receptors in each of these nuclei only transiently reduced carrageenan-induced hyperalgesia. Pharmacological activation of dopamine D2, serotonin 5-HT1A and noradrenaline alpha-2 receptors within the ACC also prevented the pronociceptive effect of sleep restriction. While pharmacological inhibition of these same monoaminergic receptors in the ACC restored the pronociceptive effect which had been prevented by the GABAergic disinhibition of the of the VTA, DRN or LC. Overall, these findings suggest that the pronociceptive effect of sleep restriction relies on increased adenosinergic activity on NAc, heightened GABAergic activity in VTA, DRN, and LC, and reduced inhibitory monoaminergic activity on ACC. These findings advance our understanding of the interplay between sleep and pain, shedding light on potential NAc-brainstem-ACC mechanisms that could mediate increased pain sensitivity under conditions of sleep impairment.

OBJECTIVE: To assess the importance of appropriate opioid administration methods according to nociceptive monitoring.
METHODS: We conducted a randomized controlled trial involving 54 patients who underwent robot-assisted laparoscopic radical prostatectomy at our hospital. Patients were randomly allocated to either receive nociception level (NOL)-directed intraoperative opioid management with a minimum flow of remifentanil (NOL group) or conventional intraoperative analgesic management (control group). The primary outcome was the mean intraoperative remifentanil infusion flow rate (intraoperative remifentanil usage [μg]/ideal body weight [kg]/operation time [min]). The main secondary outcomes were plasma concentrations of three perioperative inflammatory biomarkers (interleukin-6, C-reactive protein [CRP], and cortisol levels) and postoperative pain (Numeric Rating Scale [NRS]) scores 2 h postoperatively and on postoperative days 1, 2, 3, and 7.
RESULTS: Compared with standard analgesia management, NOL-directed analgesic management reduced remifentanil consumption by 20% ( - 0.038; 95% confidence interval, - 0.059 to - 0.017; p = 0.0007). NOL-directed management did not lead to an increase in IL-6, CRP, or cortisol levels compared with conventional analgesic management. Furthermore, this protocol led to improvements in the NRS scores at rest 2 h postoperatively and upon movement up to postoperative day 3.
CONCLUSIONS: NOL-directed analgesic management reduced remifentanil consumption by 20% and the NRS scores at rest 2 h postoperatively and upon movement up to postoperative day 3 without an increase in inflammatory marker levels.
UNASSIGNED: Japan Registry of Clinical Trials, JRCTs052220034.

This study assessed the analgesic and motor effects of the GIN-TONIC block, a combination of the greater ischiatic notch plane block and the caudal lateral quadratus lumborum block, in 24 dogs undergoing pelvic limb surgery. Dogs were randomly divided into two equal groups: GA received acepromazine [(20 µg kg-1 intravenously (IV)] as premedication, and GD received dexmedetomidine (2 µg kg-1 IV). General anesthesia was maintained with isoflurane, and both groups received a GIN-TONIC block using 2% lidocaine. Nociception during surgery and postoperative pain [assessed using the Glasgow Composite Measure Pain Score (GCMPS-SF)] were assessed. Fentanyl (2 µg kg-1 IV) was administered if nociception was noted and morphine (0.5 mg kg-1 IV) was administered during recovery if the pain scores exceeded the predefined threshold. Motor function was assessed during the recovery period using descriptors previously reported. All dogs received analgesics at the 4 h mark before being discharged. Three and two dogs in GD and GA required fentanyl once. Postoperative pain scores remained ≤4/20 for all dogs except one. Dogs achieved non-ataxic ambulation within 38.9 ± 10.3 and 35.1 ± 11.1 min after extubation in GD and GA, respectively. This study highlighted the potential of the GIN-TONIC block as a feasible regional anesthesia method for delivering perioperative analgesia in dogs undergoing pelvic limb orthopedic surgery.

Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E2 (PGE2). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT1B isamoltan, 5-HT1D BRL15572, 5-HT2A ketanserin, 5-HT3 ondansetron, but not by selective receptor antagonist 5-HT7 SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.

Nutrition can play a pivotal role in the management of pain associated with chronic rheumatic diseases. There is a growing body of research linking certain nutrients from the diet to inflammation. Certain nutrients have been shown to improve pain associated with inflammation. Furthermore, certain dietary patterns have been shown to improve pain across multiple rheumatic conditions. Finally, maintaining a low body mass is associated with improved pain associated with chronic rheumatic diseases.

The skin-brain axis has been suggested to play a role in several pathophysiological conditions, including opioid addiction, Parkinson\'s disease and many others. Recent evidence suggests that pathways regulating skin pigmentation may directly and indirectly regulate behaviour. Conversely, CNS-driven neural and hormonal responses have been demonstrated to regulate pigmentation, e.g., under stress. Additionally, due to the shared neuroectodermal origins of the melanocytes and neurons in the CNS, certain CNS diseases may be linked to pigmentation-related changes due to common regulators, e.g., MC1R variations. Furthermore, the HPA analogue of the skin connects skin pigmentation to the endocrine system, thereby allowing the skin to index possible hormonal abnormalities visibly. In this review, insight is provided into skin pigment production and neuromelanin synthesis in the brain and recent findings are summarised on how signalling pathways in the skin, with a particular focus on pigmentation, are interconnected with the central nervous system. Thus, this review may supply a better understanding of the mechanism of several skin-brain associations in health and disease.

Glutamate functions as the major excitatory neurotransmitter for primary sensory neurons and has a crucial role in sensitizing peripheral nociceptor terminals producing sensitization. Glutaminase (GLS) is the synthetic enzyme that converts glutamine to glutamate. GLS-immunoreactivity (-ir) and enzyme activity are elevated in dorsal root ganglion (DRG) neuronal cell bodies during chronic peripheral inflammation, but the mechanism for this GLS elevation is yet to be fully characterized. It has been well established that, after nerve growth factor (NGF) binds to its high-affinity receptor tropomyosin receptor kinase A (TrkA), a retrograde signaling endosome is formed. This endosome contains the late endosomal marker Rab7GTPase and is retrogradely transported via axons to the cell soma located in the DRG. This complex is responsible for regulating the transcription of several critical nociceptive genes. Here, we show that this retrograde NGF signaling mediates the expression of GLS in DRG neurons during the process of peripheral inflammation. We disrupted the normal NGF/TrkA signaling in adjuvant-induced arthritic (AIA) Sprague Dawley rats by the pharmacological inhibition of TrkA or blockade of Rab7GTPase, which significantly attenuated the expression of GLS in DRG cell bodies. The results indicate that NGF/TrkA signaling is crucial for the production of glutamate and has a vital role in the development of neurogenic inflammation. In addition, our pain behavioral data suggest that Rab7GTPase can be a potential target for attenuating peripheral inflammatory pain.

Opioid-free anesthesia (OFA) is a heterogeneous group of general anesthesia techniques in which the intraoperative use of opioids is eliminated. This strategy aims to decrease the risk of complications and improve the patient\'s safety and comfort. Such potential advantages are particularly beneficial for selected groups of patients, among them obese patients undergoing laparoscopic bariatric surgery. Opioids have been traditionally used as an element of balanced anesthesia, and replacing them requires using a combination of coanalgesics and various types of local and regional anesthesia, which also have their side effects, limitations, and potential disadvantages. Moreover, despite the growing amount of evidence, the empirical data on the superiority of OFA compared to standard anesthesia with multimodal analgesia are contradictory, and potential benefits in many studies are being questioned. Additionally, little is known about the long-term sequelae of such a strategy. Considering the above-mentioned issues, this study aims to present the potential benefits, risks, and difficulties of implementing OFA in bariatric surgery, considering the current state of knowledge and literature.