Neurokinin1 - cholinergic receptor mechanisms in the medial Septum-Dorsal hippocampus axis mediates experimental neuropathic pain.

The neurokinin-1 receptors (NK1Rs) in the forebrain medial septum (MS) region are localized exclusively on cholinergic neurons that partly project to the hippocampus and the cingulate cortex (Cg), regions implicated in nociception. In the present study, we explored the hypothesis that neurotransmission at septal NK1R and hippocampal cholinergic mechanisms mediate experimental neuropathic pain in the rodent chronic constriction injury model (CCI). Our investigations showed that intraseptal microinjection of substance P (SP) in rat evoked a peripheral hypersensitivity (PH)-like response in uninjured animals that was attenuated by systemic atropine sulphate, a muscarinic-cholinergic receptor antagonist. Conversely, pre-emptive destruction of septal cholinergic neurons attenuated the development of PH in the CCI model that also prevented the expression of cellular markers of nociception in the spinal cord and the forebrain. Likewise, anti-nociception was evoked on intraseptal microinjection of L-733,060, an antagonist at NK1Rs, and on bilateral or unilateral microinjection of the cholinergic receptor antagonists, atropine or mecamylamine, into the different regions of the dorsal hippocampus (dH) or on bilateral microinjection into the Cg. Interestingly, the effect of L-733,060 was accompanied with a widespread decreased in levels of CCI-induced nociceptive cellular markers in forebrain that was not secondary to behaviour, suggesting an active modulation of nociceptive processing by transmission at NK1R in the medial septum. The preceding suggest that the development and maintenance of neuropathic nociception is facilitated by septal NK1R-dH cholinergic mechanisms which co-ordinately affect nociceptive processing in the dH and the Cg. Additionally, the data points to a potential strategy for pain modulation that combines anticholinergics and anti-NKRs.

Enhanced labor pain monitoring using machine learning and ECG waveform analysis for uterine contraction-induced pain.

OBJECTIVES: This study aims to develop an innovative approach for monitoring and assessing labor pain through ECG waveform analysis, utilizing machine learning techniques to monitor pain resulting from uterine contractions. METHODS: The study was conducted at National Taiwan University Hospital between January and July 2020. We collected a dataset of 6010 ECG samples from women preparing for natural spontaneous delivery (NSD). The ECG data was used to develop an ECG waveform-based Nociception Monitoring Index (NoM). The dataset was divided into training (80%) and validation (20%) sets. Multiple machine learning models, including LightGBM, XGBoost, SnapLogisticRegression, and SnapDecisionTree, were developed and evaluated. Hyperparameter optimization was performed using grid search and five-fold cross-validation to enhance model performance. RESULTS: The LightGBM model demonstrated superior performance with an AUC of 0.96 and an accuracy of 90%, making it the optimal model for monitoring labor pain based on ECG data. Other models, such as XGBoost and SnapLogisticRegression, also showed strong performance, with AUC values ranging from 0.88 to 0.95. CONCLUSIONS: This study demonstrates that the integration of machine learning algorithms with ECG data significantly enhances the accuracy and reliability of labor pain monitoring. Specifically, the LightGBM model exhibits exceptional precision and robustness in continuous pain monitoring during labor, with potential applicability extending to broader healthcare settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04461704.

Decrease of the peak heights of EEG bicoherence indicated insufficiency of analgesia during surgery under general anesthesia.

BACKGROUND: Studies show that the two peak heights of electroencephalographic bicoherence (pBIC-high, pBIC-low) decrease after incision and are restored by fentanyl administration. We investigated whether pBICs are good indicators for adequacy of analgesia during surgery. METHODS: After local ethical committee approval, we enrolled 50 patients (27-65 years, ASA-PS I or II) who were scheduled elective surgery. Besides standard anesthesia monitors, to assess pBICs, we used a BIS monitor and freeware Bispectrum Analyzer for A2000. Fentanyl 5 µg/kg was completely administered before incision, and anesthesia was maintained with sevoflurane. After skin incision, when the peak of pBIC-high or pBIC-low decreased by 10% in absolute value (named LT10-high and LT10-low groups in order) or when either peak decreased to below 20% (BL20-high and BL20-low groups), an additional 1 g/kg of fentanyl was administered to examine its effect on the peak that showed a decrease. RESULTS: The mean values and standard deviation for pBIC-high 5 min before fentanyl administration, at the time of fentanyl administration, and 5 min after fentanyl administration for LT10-high group were 39.8% (10.9%), 26.9% (10.5%), and 35.7% (12.5%). And those for pBIC-low for LT10-low group were 39.5% (6.0%), 26.8% (6.4%) and 35.0% (7.0%). Those for pBIC-high for BL20-high group were 26.3% (5.6%), 16.5% (2.6%), and 25.7% (7.0%). And those for pBIC-low for BL20-low group were 26.7% (4.8%), 17.4% (1.8%) and 26.9% (5.7%), respectively. Meanwhile, at these trigger points, hemodynamic parameters didn't show significant changes. CONCLUSION: Superior to standard anesthesia monitoring, pBICs are better indicators of analgesia during surgery. TRIAL REGISTRY: Clinical trial Number and registry URL: UMIN ID: UMIN000042843 https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno = R000048907.

Use of a shuttle box model to assess the behavioral and analgesic effects of opioid injections in goldfish (Carassius auratus).

OBJECTIVE: To evaluate if opioid-induced behavioral effects, such as sedation, can be detected using a shuttle box experimental apparatus and whether thermal preference following noxious stimulation using mustard oil is reversed by morphine administration in fish. METHODS: 5 goldfish (Carassius auratus) underwent 2 randomized blinded experimental trials, with a crossover study design. First, opioid effects were tested in a shuttle box without painful stimulus. Fish were injected 5 days apart with butorphanol at 0.4 or 10 mg/kg, morphine at 5 or 10 mg/kg, or saline IM. After 30 minutes, each fish was placed in a shuttle box for 2 hours with a temperature gradient of 26 to 28 °C. Temperature preference, time spent immobile, and swimming velocity were assessed. The second trial consisted of cutaneous noxious stimulation using mustard oil immersion for 5 minutes followed by an assessment of thermal preference for 4 minutes in the shuttle box after either morphine at 10 mg/kg or saline IM injections. Linear mixed models were used to compare treatment groups. RESULTS: Before noxious stimulation, a low dose of morphine caused sedation compared with control group and high-dose morphine and butorphanol treatments. Immersion in mustard oil caused fish to spend more time in the cold area in the control group. Morphine administration reversed this pattern. CONCLUSIONS: The sedative and analgesic effects of opioids were detected through this model. CLINICAL RELEVANCE: The shuttle box model could be used to assess the analgesic effects of other opioids in goldfish while reducing biases associated with the sedative and stimulatory effects of these drugs.

Nociception level index variations in ICU: curarized vs non-curarized patients - a pilot study.

PURPOSE: Pain is a major physiological stressor that can worsen critical medical conditions in many ways. Currently, there is no reliable monitoring tool which is available for pain monitoring in the deeply sedated ± curarized critically ill patients. This study aims to assess the effectiveness of the multiparameter nociception index (NOL®) in the critical care setting. We compared NOL with traditionally used neurovegetative signs and examined its correlation with sedation depth measured by bispectral index (BIS®) electroencephalographic (EEG) monitoring. METHODS: This retrospective monocentric cohort study was conducted in a general intensive care unit, including patients who required moderate-to-deep levels of sedation with or without continuous neuromuscular blockade. The performance of NOL was evaluated both in the entire studied population, as well as in two subgroups: curarized and non-curarized patients. RESULTS: NOL demonstrated greater accuracy than all other indicators in pain detection in the overall population. In the non-curare subgroup, all indices correctly recognized painful stimulation, while in the patients subjected to neuromuscular blocking agent's infusion, only NOL properly identified nociception. In the former group, EEG's relation to nociception was on the border of statistical significance, whereas in the latter BIS showed no correlation with NOL. CONCLUSION: NOL emerges as a promising device for pain assessment in the critical care setting and exhibits its best performance precisely in the clinical context where reliable pain assessment methods are most lacking. Furthermore, our research confirms the distinction between sedation and analgesia, highlighting the necessity for distinct monitoring instruments to accurately assess them.

Heeding Pain's Prescription.

Newer definitions of pain remain suggestive of categorization by mainly neurological or psychological bases. All pain recruits cortical interpretation for any sort of directive effects in awareness, attention, and action. That unity of purpose in pain's multi-pathway manifestations can inspire neurophilosophical reflections on the existentiality, subjectivity, and sociality of pain. Pain is neither so subjective as to be relieved of meaning, nor so objective that multi-modal approaches can take turns at targeting its relief. The problem of objectifying the subjective is essential for addressing issues of assessing and treating pain. Integrative plans for pain care make sense if and when all aspects of pain's character are deemed to be integral, and are actually integrated in both theory in practice. A standpoint on the "entity-identity" of pain afflicting the whole person implies that pain is expressed behaviorally and as articulately as circumstances permit. Pain speaks, even for those not able to speak, as their patterns of brain activity may be representative of pain. Heeding pain's prescriptive voice requires collective interpretations before attempting coordinated treatments. Pain's prescription will remain unfilled until its full reality is recognized at a personal level, where comprehensive care is mobilized for the whole patient. Heeding pain looks to the central figure that is never absent from any painful situation, namely the individual person-in-pain. That holistic and humanistic value to mobilizing resources against pain should be reflected in the practice of pain medicine, and the craft of the pain physician.

Transcriptional reprogramming post-peripheral nerve injury: A systematic review.

Neuropathic pain is characterised by periodic or continuous hyperalgesia, numbness, or allodynia, and results from insults to the somatosensory nervous system. Peripheral nerve injury induces transcriptional reprogramming in peripheral sensory neurons, contributing to increased spinal nociceptive input and the development of neuropathic pain. Effective treatment for neuropathic pain remains an unmet medical need as current therapeutics offer limited effectiveness and have undesirable effects. Understanding transcriptional changes in peripheral nerve injury-induced neuropathy might offer a path for novel analgesics. Our literature search identified 65 papers exploring transcriptomic changes post-peripheral nerve injury, many of which were conducted in animal models. We scrutinize their transcriptional changes data and conduct gene ontology enrichment analysis to reveal their common functional profile. Focusing on genes involved in 'sensory perception of pain' (GO:0019233), we identified transcriptional changes for different ion channels, receptors, and neurotransmitters, shedding light on its role in nociception. Examining peripheral sensory neurons subtype-specific transcriptional reprograming and regeneration-associated genes, we delved into downstream regulation of hypersensitivity. Identifying the temporal program of transcription regulatory mechanisms might help develop better therapeutics to target them effectively and selectively, thus preventing the development of neuropathic pain without affecting other physiological functions.

Establishing a standardised approach for the measurement of neonatal noxious-evoked brain activity in response to an acute somatic nociceptive heel lance stimulus.

BACKGROUND: Electroencephalography (EEG) can be used in neonates to measure brain activity changes that are evoked by noxious events, such as clinically required immunisations, cannulation and heel lancing for blood tests. EEG provides an alternative approach to infer pain experience in infants compared with more commonly used behavioural and physiological pain assessments. Establishing the generalisability and construct validity of these measures will help corroborate the use of brain-derived outcomes to evaluate the efficacy of new or existing pharmacological and non-pharmacological methods to treat neonatal pain. This study aimed to test whether a measure of noxious-evoked EEG activity called the noxious neurodynamic response function (n-NRF), that was originally derived in a sample of term-aged infants at the Oxford John Radcliffe Hospital, UK, in 2017, can reliably distinguish noxious from non-noxious events in two independent datasets collected at University College London Hospital and at Royal Devon & Exeter Hospital. We aimed to reproduce three published results that use this measure to quantify noxious-evoked changes in brain activity. We used the n-NRF to quantify noxious-evoked brain activity to test (i) whether significantly larger noxious-evoked activity is recorded in response to a clinical heel lance compared to a non-noxious control heel lance procedure; (ii) whether the magnitude of the activity evoked by a noxious heel lance is equivalent in independent cohorts of infants; and (iii) whether the magnitude of the noxious-evoked brain activity increases with postmenstrual age (PMA) in premature infants up to 37 weeks PMA. Positive replication of these studies will build confidence in the use of the n-NRF as a valid and reliable pain-related outcome which could be used to evaluate analgesic efficacy in neonates. The protocol for this study was published following peer review (https://doi.org/10.17605/OSF.IO/ZY9MS). RESULTS: The n-NRF magnitude to a noxious heel lance stimulus was significantly greater than to a non-noxious control heel lance stimulus in both the UCL dataset (n = 60; mean difference .88; 95% confidence interval (CI) .64-1.13; p < .0001) and the Exeter dataset (n = 31; mean difference .31; 95% CI .02-.61; p = .02). The mean magnitude and 90% bootstrap confidence interval of the n-NRF evoked by the heel lance did not meet our pre-defined equivalence bounds of 1.0 ± .2 in either the UCL dataset (n = 72; mean magnitude 1.33; 90% bootstrapped CI 1.18-1.52) or the Exeter dataset (n = 35; mean magnitude .92, 90% bootstrapped CI .74-1.22). The magnitude of the n-NRF to the noxious stimulus was significantly positively correlated with PMA in infants up to 37 weeks PMA (n = 65; one-sided Pearson's R, adjusted for site: .24; 95% CI .06-1.00; p = .03). CONCLUSIONS: We have reproduced in independent datasets the findings that the n-NRF response to a noxious stimulus is significantly greater than to a non-noxious stimulus, and that the noxious-evoked EEG response increases with PMA. The pre-defined equivalence bounds for the mean magnitude of the EEG response were not met, though this might be due to either inter-site differences such as the lack of calibration of devices between sites (a true negative) or underpowering (a false negative). This reproducibility study provides robust evidence that supports the use of the n-NRF as an objective outcome for clinical trials assessing acute nociception in neonates. Use of the n-NRF in this way has the potential to transform the way analgesic efficacy studies are performed.

High frequency variability index in predicting postoperative pain in video/robotic-assisted thoracoscopic surgery under combined general anesthesia and peripheral nerve block: an observational study.

The high frequency variability index (HFVI)/analgesia nociception index (ANI) is purported to assess the balance between nociception and analgesia in patients under general anesthesia. This observational study investigated whether intraoperative HFVI/ANI correlates with postoperative pain in patients performed with nerve block under general anesthesia in video/robotic-assisted thoracoscopic surgery (VATS/RATS). We investigated whether maximum postoperative pain at rest and postoperative morphine consumption are associated with HFVI/ANI just before extubation, mean HFVI/ANI during anesthesia, the difference in HFVI/ANI between before and 5 min after the start of surgery, and the difference in HFVI/ANI between before and 5 min after the nerve block. Data obtained from 48 patients were analyzed. We found no significant association between HFVI/ANI just before extubation and postoperative Numerical Rating Scale (NRS) score. Receiver operating characteristic curve analysis revealed that moderate (NRS > 3) or severe (NRS > 7) postoperative pain could not be predicted by HFVI/ANI just before extubation. In addition, there were no associations between postoperative morphine consumption and HFVI/ANI at any time points. The present study demonstrated that it is difficult to predict the degree of postoperative pain in patients undergoing VATS/RATS under general anesthesia combined with peripheral nerve block, by using HFVI/ANI obtained at multiple time points during general anesthesia.

Analysis of the Effects of Epidural Anesthesia on the Nociception Level Index (NOL®) during Abdominal Surgery.

Background: The NOL® system (PMD-200™ Nociception Level Monitor; Medasense Ltd., Ramat Gan, Israel) is used for the real-time detection of physiological nociception in anesthetized patients by assessing the parameters indicative of sympathetic activity, such as photoplethysmography, skin conductance, peripheral temperature, and accelerometry, which are quantified into the NOL®-Index. This index is more sensitive than traditional clinical parameters in estimating pain and stress responses. While its effectiveness in general anesthesia is well documented, its efficacy in epidural anesthesia needs further investigation. Methods: This retrospective study analyzed NOL®-Index dynamics compared to conventional parameters after epidural administration of bupivacaine. Following ethics committee approval, 119 NOL® measurements were retrospectively analyzed after thoracic epidural catheter administration in 40 patients undergoing abdominal and urological surgery. The NOL-Index® was assessed at 0, 1, 3, and 5 min post application and compared to heart rate, blood pressure, and bispectral index dynamics. Results: This study showed a significant decrease in the NOL®-Index post-local-anesthetic administration with better sensitivity than classical clinical parameters (0 min = 38 ± 11; 1 min = 22 ± 13*; 3 min = 17 ± 11*; 5 min = 12 ± 10*). Higher doses of local anesthetics led to a significant, dose-dependent decrease in NOL®-Index (low dose, 5 min = 15 ± 10*; high dose, 5 min = 8 ± 8*). Conclusions: This study is the first to demonstrate the effectiveness of the NOL®-Index in measuring nociceptive effects following epidural administration, highlighting its potential superiority over conventional parameters and its sensitivity to dose variations.

The Phytochemical, Quercetin, Attenuates Nociceptive and Pathological Pain: Neurophysiological Mechanisms and Therapeutic Potential.

Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side effects. Quercetin is a flavonoid that is widely found in fruits and vegetables. Since recent studies have demonstrated that quercetin can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission via mechanoreceptors and voltage-gated ion channels, and inhibit the cyclooxygenase-2-cascade, it is possible that quercetin could be a complementary alternative medicine candidate; specifically, a therapeutic agent against nociceptive and pathological pain. The focus of this review is to elucidate the neurophysiological mechanisms underlying the modulatory effects of quercetin on nociceptive neuronal activity under nociceptive and pathological conditions, without inducing side effects. Based on the results of our previous research on trigeminal pain, we have confirmed in vivo that the phytochemical, quercetin, demonstrates (i) a local anesthetic effect on nociceptive pain, (ii) a local anesthetic effect on pain related to acute inflammation, and (iii) an anti-inflammatory effect on chronic pain. In addition, we discuss the contribution of quercetin to the relief of nociceptive and inflammatory pain and its potential clinical application.

Cue-based modulation of pain stimulus expectation: do ongoing oscillations reflect changes in pain perception? A registered report.

A promising stream of investigations is targeting ongoing neural oscillations and whether their modulation could be related to the perception of pain. Using an electroencephalography (EEG) frequency-tagging approach, sustained periodic thermonociceptive stimuli perceived as painful have been shown to modulate ongoing oscillations in the theta, alpha and beta bands at the frequency of stimulation. Nonetheless, it remains uncertain whether these modulations are indeed linked to pain perception. To test this relationship, we modulated pain perception using a cue-based expectation modulation paradigm and investigated whether ongoing oscillations in different frequency bands mirror the changes in stimulus perception. Forty healthy participants were instructed that a visual cue can precede either a high- or low-intensity stimulation. These cues were paired with three different levels of sustained periodic thermonociceptive stimuli (low, medium and high). Despite a strong effect of expectation on perceived stimulus intensity, this effect was not reflected in the modulation of the ongoing oscillations, suggesting a potential dissociation of pain perception and these oscillatory activities. Rather, it seems that the intensity of stimulation is the primary generator of the frequency-tagged EEG responses. Importantly, these results need to be confirmed by further investigations that could allow the detection of smaller effects than originally estimated.

Antivenom potential of the latex of Jatropha mutabilis baill. (Euphorbiaceae) against Tityus stigmurus venom: Evaluating its ability to neutralize toxins and local effects in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Species of the Jatropha genus (Euphorbiaceae) are used indiscriminately in traditional medicine to treat accidents involving venomous animals. Jatropha mutabilis Baill., popularly known as "pinhão-de-seda," is found in the semi-arid region of Northeastern Brazil. It is widely used as a vermifuge, depurative, laxative, and antivenom. AIM OF THE STUDY: Obtaining the phytochemical profile of the latex of Jatropha mutabilis (JmLa) and evaluate its acute oral toxicity and inhibitory effects against the venom of the scorpion Tityus stigmurus (TstiV). MATERIALS AND METHODS: The latex of J. mutabilis (JmLa) was obtained through in situ incisions in the stem and characterized using HPLC-ESI-QToF-MS. Acute oral toxicity was investigated in mice. The protein profile of T. stigmurus venom was obtained by electrophoresis. The ability of latex to interact with venom components (TstiV) was assessed using SDS-PAGE, UV-Vis scanning spectrum, and the neutralization of fibrinogenolytic and hyaluronidase activities. Additionally, the latex was evaluated in vivo for its ability to inhibit local edematogenic and nociceptive effects induced by the venom. RESULTS: The phytochemical profile of the latex revealed the presence of 75 compounds, including cyclic peptides, glycosides, phenolic compounds, alkaloids, coumarins, and terpenoids, among others. No signs of acute toxicity were observed at a dose of 2000 mg/kg (p.o.). The latex interacted with the protein profile of TstiV, inhibiting the venom's fibrinogenolytic and hyaluronidase activities by 100%. Additionally, the latex was able to mitigate local envenomation effects, reducing nociception by up to 56.5% and edema by up to 50% compared to the negative control group. CONCLUSIONS: The latex of Jatropha mutabilis exhibits a diverse phytochemical composition, containing numerous classes of metabolites. It does not present acute toxic effects in mice and has the ability to inhibit the enzymatic effects of Tityus stigmurus venom in vitro. Additionally, it reduces nociception and edema in vivo. These findings corroborate popular reports regarding the antivenom activity of this plant and indicate that the latex has potential for treating scorpionism.

Antinociceptive and anesthetic-sparing effects of levomethadone/fenpipramide cannot be enhanced by coadministration of metamizole in awake and anesthetized Beagles.

OBJECTIVE: To determine the effect of levomethadone/fenpipramide and metamizole alone and in combination on acute nociception. METHODS: 8 healthy, adult Beagles were used in 2 separate randomized, complete crossover, experimental trials (threshold testing and determination of minimal alveolar concentration [MAC]) with masked observers. In both trials, treatments were 0.2 mg·kg-1 levomethadone/fenpipramide (L), 75 mg·kg-1 metamizole (M), or their combination (LM). In conscious dogs, mechanical thresholds were determined using constantly rising force. Thermal thresholds were measured via ramped contact heat. The MAC of sevoflurane was determined using the bracketing method with electrical stimulus (50 V, 50 Hz, 10 ms) before and 1 and 4 hours after treatment. RESULTS: Mechanical thresholds in L and LM were significantly increased above baseline (BL) for 165 minutes and above M for 135 minutes. Percent thermal threshold excursion significantly increased above BL in L for 75 minutes and in LM for 135 minutes. In L and LM, the percent thermal threshold excursion was significantly higher than in M from 15 to 75 or 135 minutes, respectively. In L and LM, the MAC of sevoflurane was significantly reduced at 1 hour compared to BL and M. CONCLUSION: Duration but not the magnitude of thermal antinociception of levomethadone/fenpipramide was increased by metamizole. Mechanical antinociception in awake dogs and anesthetic-sparing effects of levomethadone/fenpipramide were not altered. CLINICAL RELEVANCE: Coadministration of levomethadone/fenpipramide and metamizole to increase antinociception is not justified.

Preface to the special issue "Pain".

This preface introduces the Journal of Neurochemistry Special Issue on pain research. While acute pain provides important sensory information, which aids in the protection of an organism, it can in some cases transition into a chronic state. Unfortunately, chronic pain is a highly disabling state characterised by intense and abnormal pain sensations, which are exacerbated by problematic psychosocial disturbances that are poorly treated by current drugs. This issue includes several reviews that address current issues spanning basic to clinical research on a range of pain syndromes. Also included is a collection of basic research articles investigating important aspects of pain signalling through to whole body aspects of pain integration.

Assessment of the nociceptive response to the use of cannabidiol alone and in combination with meloxicam through infrared pupillometry in female dogs undergoing elective ovariohysterectomy.

The negative effects of pain are a constant concern in the surgical management of animals, leading to the search for new drugs or more effective analgesic protocols to control this negative emotion. This study aimed to evaluate the nociceptive response of cannabidiol (CBD) alone and in combination with meloxicam using infrared pupillometry in female dogs undergoing elective ovariohysterectomy (OVH) under isoflurane anesthesia. A total of 60 female dogs of different breeds were included. These dogs were randomly assigned to four study groups according to the treatment: Control Group (G0: n = 15) receiving saline solution; group premedicated with meloxicam at a dose of 0.2 mg Kg-1 IV (GMelox: n = 15). Postoperatively this drug was used at 0.1 mg Kg-1 IV every 24 h; the CBD-treated Group (GCBD: n = 15) at a dose of 2 mg Kg-1 orally in the preoperative. Postoperatively was administrated every 12 h; and the Group premedicated with the combination of meloxicam and CBD (GMelox/CBD: n = 15) Meloxicam at a dose of 0.2 mg Kg-1 IV preoperatively, and 0.1 mg Kg-1 IV during the postoperative. CBD at a dose of 2 mg Kg-1 orally in the preoperative, and every 12 h in the postoperative. Treatments were administered for 48 postoperative hours. After OVH, the pupillary neurologic index, pupillary size, minimum diameter (MIN), percentage change, constriction latency (Lat), constriction velocity, and maximum constriction velocity were recorded as pupillometric variables in both eyes during events (E): Baseline (30 min before drug administration), E30 min, E1h, E2h, E3h, E4h, E8h, E12h, E24h, and E48h. The Short-Form of the Glasgow Composite Measure Pain Scale (GCMPS-SF) was used to assess pain during the same events. Overall, it was observed that the pupillometric variables Size, MIN., and Lat. were significantly higher in G0 compared to the other groups during E30 min, E1h, and E2h (p = 0.03), indicating greater pupil dilation in G0 animals. Additionally, no statistically significant differences were observed in GCMPS-SF between GMelox, GCBD, and GMelox/CBD during the postoperative period (p > 0.05). In contrast, the scores were statistically different compared to G0 (p = 0.00001), where all animals in this group received rescue analgesia at 2 h post-surgery. According to pupillometry and scores on the GCMPS-SF scale, it was observed that monotherapy with cannabidiol provides a similar analgesic effect to meloxicam alone or in combination with cannabidiol to manage acute pain in dogs. Similarly, these findings suggest that infrared pupillometry could be a tool for recognizing acute pain in dogs.

SGIP1 Deletion in Mice Attenuates Mechanical Hypersensitivity Elicited by Inflammation.

Background: Activation of cannabinoid receptor 1 (CB1R) in the nervous system modulates the processing of acute and chronic pain. CB1R activity is regulated by desensitization and internalization. SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1) inhibits the internalization of CB1R. This causes increased and prolonged association of the desensitized receptor with G protein-coupled receptor kinase 3 (GRK3) and beta-arrestin on the cell membrane and results in decreased activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Genetic deletion of SGIP1 in mice leads to altered CB1R-related functions, such as decreased anxiety-like behaviors, modified cannabinoid tetrad behaviors, reduced acute nociception, and increased sensitivity to analgesics. In this work, we asked if deletion of SGIP1 affects chronic nociception and analgesic effect of Δ9-tetrahydrocannabinol (THC) and WIN 55,212-2 (WIN) in mice. Methods: We measured tactile responses of hind paws to increasing pressure in wild-type and SGIP1 knock-out mice. Inflammation in the paw was induced by local injection of carrageenan. To determine the mechanical sensitivity, the paw withdrawal threshold (PWT) was measured using an electronic von Frey instrument with the progression of the applied force. Results: The responses to mechanical stimuli varied depending on the sex, genotype, and treatment. SGIP1 knock-out male mice exhibited lower PWT than wild-type males. On the contrary, the female mice exhibited comparable PWT. Following THC or WIN treatment in male mice, SGIP1 knock-out males exhibited PWT lower than wild-type males. THC treatment in SGIP1 knock-out females resulted in PWT higher than after THC treatment of wild-type females. However, SGIP1 knock-out and wild-type female mice exhibited similar PWT after WIN treatment. Conclusions: We provide evidence that SGIP1, possibly by interacting with CB1R, is involved in processing the responses to chronic pain. The absence of SGIP1 results in enhanced sensitivity to mechanical stimuli in males, but not females. The antinociceptive effect of THC is superior to that of WIN in SGIP1 knock-out mice in the carrageenan-induced model of chronic pain.

Evaluation of the Therapeutic Potential of Amantadine in a Vincristine-Induced Peripheral Neuropathy Model in Rats.

This study aimed to evaluate the therapeutic potential of amantadine in a vincristine-induced peripheral neuropathy model in rats. Forty-eight male Wistar rats were used. The treated groups received oral amantadine at doses of 2, 5, 12, 25 and 50 mg/kg, with daily applications for 14 days. The mechanical paw withdrawal threshold was measured using a digital analgesimeter. Immunohistochemical analysis of IL-6, TNFα, MIP1α, IL-10, CX3CR1, CXCR4, SOD, CAT and GPx, and enzymatic activity analysis of CAT, SOD and GPx were performed, in addition to quantitative PCR of Grp78, Chop, Ho1, Perk, Bax, Bcl-xL, Casp 3, Casp 9, IL-6, IL-10, IL-18 and IL-1ß. The results showed an increase in nociceptive thresholds in animals that received 25 mg/kg and 50 mg/kg amantadine. Immunohistochemistry showed a decrease in the immunostaining of IL-6, TNFα, MIP1α and CX3CR1, and an increase in IL-10. CAT and SOD showed an increase in both immunochemistry and enzymatic analysis. qPCR revealed a reduced expression of genes related to endoplasmic reticulum stress and regulation in the expression of immunological and apoptotic markers. Amantadine demonstrated antinociceptive, anti-inflammatory and antioxidant effects in the vincristine-induced peripheral neuropathy model in rats, suggesting that amantadine may be considered an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

The effects of eating a traditional high fat/high carbohydrate or a ketogenic diet on sensitivity of female rats to morphine.

Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (n=8/diet) ate either a standard laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32-56 mg/kg, IP) injections. Morphine was administered acutely and chronically, which involved 19 days of twice daily injections (increasing in 1/4 log dose increments every 3 days: 3.2-56 mg/kg, IP) to induce dependence and assess tolerance. The adverse effects of morphine (i.e., tolerance, withdrawal, changes in body temperature) were assessed throughout the study. Morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Additional adverse effects of morphine were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss, in ways that could be relevant for patients. Significance Statement The present study in female rats suggests that eating a high fat/low carbohydrate (ketogenic) or a traditional high fat/high carbohydrate diet does not impact the pain-relieving or adverse effects of opioids (i.e., tolerance or withdrawal). However, eating a ketogenic diet may have beneficial effects on opioid withdrawal-related weight loss. Individuals diagnosed with obesity taking opioids for pain-related conditions might therefore consider adopting a ketogenic diet when opioid administration is discontinued to potentially mitigate withdrawal-related weight loss.

Vitamin B5 is a context-dependent dietary regulator of nociception.

Chronic pain has an enormous impact on the quality of life of billions of patients, families, and caregivers worldwide. Current therapies do not adequately address pain for most patients. A basic understanding of the conserved genetic framework controlling pain may help us develop better, non-addictive pain therapies. Here we identify new conserved and druggable analgesic targets using tissue-specific functional genomic screening of candidate "pain" genes in the fly. From these efforts we describe 23 new pain genes for further consideration. This included Acsl, a fatty acid-metabolizing enzyme and mammalian orthologs are involved in arachidonic acid metabolism. Acsl knockdown and mutant larvae showed delayed nocifensive responses to localized and global noxious heat. Mechanistically, knockdown of Acsl reduced dendritic branching of nociceptive neurons. Surprisingly, the pain phenotype in these animals could be rescued through dietary intervention with vitamin B5, highlighting the interplay between genetics, metabolism and nutrient environment to establish sensory perception thresholds. Together, our functional genomic screening within the sensory nociceptor has identified new nociception genes that provide a better understanding of pain biology and can help guide the development of new painkillers.