Systemic administration of Resolvin D1 reduces cancer-induced bone pain in mice: Lack of sex dependency in pain development and analgesia.

AIMS: Bone cancer produces severe pain that is treated with opioids, but serious side effects limit opioid utilization. There is therefore a need to develop effective and safe non-opioid alternatives. The lipid mediator, Resolvin D1 (RvD1), could be a prospective candidate for cancer pain treatment. To assess RvD1 and other potential candidates, appropriate animal models that recapitulate clinical features must be used. Although several preclinical models of cancer pain have been developed, the influence of sex on the development of cancer pain and the effectiveness of RvD1 have not been studied. RESULTS: Using a mouse model of fibrosarcoma growth in and around the calcaneus bone, we demonstrated that the mechanical hyperalgesia in the tumor-bearing hind paw develops independently of sex, except that it developed a little sooner in female mice. A single intravenous injection of RvD1 (0.001-10 µg/kg) decreased hyperalgesia in both sexes with similar potency (ED50 = 0.0015 µg/kg) and efficacy. Repeated daily administration of 10 µg/kg RvD1 prolonged the analgesic effect and completely abolished hyperalgesia. This was also independent of sex. CONCLUSION: In this preclinical mouse model of bone cancer pain, the development of pain and the analgesic effectiveness of RvD1 are not influenced by sex.

AR71, Histamine H3 Receptor Ligand-In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action).

The future of therapy for neurodegenerative diseases (NDs) relies on new strategies targeting multiple pharmacological pathways. Our research led to obtaining the compound AR71 [(E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one], which has high affinity for human H3R (Ki = 24 nM) and selectivity towards histamine H1 and H4 receptors (Ki > 2500 nM), and showed anti-inflammatory activity in a model of lipopolysaccharide-induced inflammation in BV-2 cells. The presented tests confirmed its antagonist/inverse agonist activity profile and good metabolic stability while docking studies showed the binding mode to histamine H1, H3, and H4 receptors. In in vitro tests, cytotoxicity was evaluated at three cell lines (neuroblastoma, astrocytes, and human peripheral blood mononuclear cells), and a neuroprotective effect was observed in rotenone-induced toxicity. In vivo experiments in a mouse neuropathic pain model demonstrated the highest analgesic effects of AR71 at the dose of 20 mg/kg body weight. Additionally, AR71 showed antiproliferative activity in higher concentrations. These findings suggest the need for further evaluation of AR71's therapeutic potential in treating ND and CNS cancer using animal experimental models.

Exploring the Analgesic Initiation Mechanism of Tuina in the Dorsal Root Ganglion of Minor CCI Rats via the TRPV1/TRPA1-cGMP Pathway.

Tuina is a treatment method in traditional Chinese medicine which has analgesic effects and effectively alleviates the symptoms of neuropathic pain (NP). Transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1) play major roles in transmitting nociceptive sensory signals in the nociceptive primary sensory dorsal root ganglion (DRG) nerve. The nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate(cGMP) pathway exerts both nociceptive and antinociceptive effects in various chronic pain models. TRPV1 and TRPA1 mediate the influx of calcium, which stimulates the generation of NO. Subsequently, NO activates the NO/cGMP/protein kinase G (PKG) signaling pathway, thereby improving hyperalgesia. In the present study, oa rat model of NP with minor chronic constriction injury (CCI) of the right sciatic nerve of NP was established. The results of behavioral testing showed that, after a one-time tuina intervention, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were prolonged to varying degrees in the tuina group compared with the model group. Similarly, the expression of TRPV1, TRPA1, NO, soluble guanylate cyclase ß (sGCß), cGMP, and PKG1 was significantly decreased in the DRG of the tuina and tuina + TRPV1/TRPA1 antagonist group was significantly decreased. These findings suggest that the tuina intervention can effectively improve the symptoms of thermal and mechanical allodynia caused by peripheral nerve injuries. Tuina exerts immediate analgesic effects through the TRPV1/TRPA1-NO-cGMP-PKG signaling pathway.

Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Study of PT1 Peptide Analgesic and Anti-Inflammatory Activity on a Local Inflammation Model in Mice CD-1.

PT1 peptide isolated from the venom of spider Geolycosa sp. is a modulator of P2X3 receptors that play a role in the development of inflammation and the transmission of pain impulses. The anti-inflammatory and analgesic efficacy of the PT1 peptide was studied in a model of complete Freund's adjuvant-induced paw inflammation in CD-1 mice. The analgesic activity of PT1 peptide was maximum after intramuscular injection at a dose of 0.01 mg/kg, which surpassed the analgesic effect of diclofenac at a dose of 1 mg/kg. The anti-inflammatory activity was maximum after intramuscular injection at a dose of 0.0001 mg/kg; a decrease in paw thickness was observed as soon as 2 h after the administration of the PT1 peptide against the background of inflammation development. All tested doses of PT1 peptide showed high anti-inflammatory activity 4 and 24 h after administration. PT1 peptide at a dose of 0.01 mg/kg when injected intramuscularly simultaneously produced high anti-inflammatory and analgesic effects compared to other doses of the peptide. Increasing the dose of PT1 peptide led to a gradual decrease in its analgesic and anti-inflammatory activity; increasing the dose of intramuscular injection to 0.1 and 1 mg/kg is inappropriate.

Protein Kinase A Inhibitor Attenuates the Antinociceptive Effect of NMDA-Receptor Channel Antagonists in the Capsaicin Test in Mice.

Acute nociceptive pain in mice caused by subcutaneous (intraplantar) injection of TRPV1 ion channel agonist capsaicin (1.6 µg/mouse) and the effects of protein kinase A inhibitor H-89 (0.05 mg/mouse, intraplantar injection) and NMDA receptor channel antagonists MK-801 (7.5 and 15 µg/mouse, topical application) and hemantane (0.5 mg/mouse, topical application) on the pain were assessed. MK-801 and hemantane were found to reduce the duration of the pain response. H-89 did not significantly affect the pain in animals, but preliminary administration of this drug abolished the antinociceptive effect of MK-801 (7.5 µg/mouse) and weakens the effect of hemantane (0.5 mg/mouse).

The Anti-Inflammatory, Analgesic, and Antioxidant Effects of Polyphenols from Brassica oleracea var. capitata Extract on Induced Inflammation in Rodents.

This study investigates the anti-inflammatory, analgesic, and antioxidant properties of polyphenols extracted from Brassica oleracea var. capitata (cabbage) ethanolic extract (BOE). Given the historical use of cabbage in traditional medicine for treating various ailments, this research aims to validate these effects scientifically. The study involved the characterization of BOE's bioactive compounds using Fourier Transform Infrared Spectroscopy (FTIR) and Liquid Chromatography-Diode Array Detection-Electro-Spray Ionization Mass Spectrometry (HPLC-DAD-ESI MS) analysis. We assessed the anti-inflammatory and analgesic effects of topical and oral BOE administration on rodent models with acute and subacute inflammation. Additionally, the antioxidant capacity of orally administered BOE was evaluated. The results showed that BOE possesses significant levels of phenolic compounds with a potent antioxidant activity. The topical administration of BOE demonstrated notable anti-inflammatory effects in the tested rodent models, which were comparable with nonsteroidal anti-inflammatory drugs. These findings suggest that BOE could be a valuable natural remedy for inflammation-related conditions, supporting its traditional uses and highlighting its potential for further pharmacological development.

Pain Relief, Functional Recovery, and Chondroprotective Effects of Angelica gigas Nakai in Osteoarthritis Due to Its Anti-Inflammatory Property: An In Vitro and In Vivo Study.

Osteoarthritis (OA), characterized by chronic pain and joint degradation, is a progressive joint disease primarily induced by age-related systemic inflammation. Angelica gigas Nakai (AG), a medicinal plant widely used in East Asia, exhibits promising results for such conditions. This study aimed to evaluate the potential of AG as a drug candidate for modulating the multifaceted pathology of OA based on its anti-inflammatory properties. We evaluated the efficacy of AG in pain relief, functional improvement, and cartilage erosion delay using monosodium iodoacetate-induced OA rats and acetic acid-induced writhing mice, along with its anti-inflammatory effects on multiple targets in the serum and cartilage of in vivo models and lipopolysaccharide-stimulated RAW 264.7 cells. In vivo experiments demonstrated significant analgesic and chondroprotective effects of AG, along with functional recovery, in model animals compared with the active controls. AG dose-dependently modulated inflammatory OA pathology-related targets, including interleukin-1ß, tumor necrosis factor-α, matrix metalloproteinase-13, and cyclooxygenase-2, both in vitro and in vivo. In conclusion, AG could be a potential drug candidate for modulating the multifaceted pathology of OA. Nevertheless, further comprehensive investigations, involving a broader range of compounds, pathologies, and mechanisms, are warranted to validate these findings.

Advancements in Non-Addictive Analgesic Diterpenoid Alkaloid Lappaconitine: A Review.

The perennial herb Aconitum sinomontanum Nakai (Ranunculaceae) has been utilized as a traditional oriental medicine in China for numerous years. The principal pharmacological constituent of A. sinomontanum, lappaconitine (LA), exhibits analgesic, anti-inflammatory, anti-tumor, anti-arrhythmic, and anti-epileptic activities. Due to its potent efficacy and non-addictive nature, LA is widely utilized in the management of cancer pain and postoperative analgesia. This review encompasses the research advancements pertaining to LA including extraction methods, separation techniques, pharmacological properties, chemical modifications, and clinical applications. Additionally, it offers insights into the potential applications and current challenges associated with LA to facilitate future research endeavors.

German Chamomile (Matricaria chamomilla L.) Flower Extract, Its Amino Acid Preparations and 3D-Printed Dosage Forms: Phytochemical, Pharmacological, Technological, and Molecular Docking Study.

German chamomile (Matricaria chamomilla L.) is an essential oil- containing medicinal plant used worldwide. The aim of this study was to gain knowledge of the phytochemical composition and the analgesic and soporific activity of Matricaria chamomilla L. (German chamomile) flower extract and its amino acid preparations, to predict the mechanisms of their effects by molecular docking and to develop aqueous printing gels and novel 3D-printed oral dosage forms for the flower extracts. In total, 22 polyphenolic compounds and 14 amino acids were identified and quantified in the M. chamomilla extracts. In vivo animal studies with rodents showed that the oral administration of such extracts revealed the potential for treating of sleep disorders and diseases accompanied by pain. Amino acids were found to potentiate these effects. Glycine enhanced the analgesic activity the most, while lysine and ß-alanine improved the soporific activity. The molecular docking analysis revealed a high probability of γ-aminobutyric acid type A (GABAA) and N-methyl-D-aspartate (NMDA) receptor antagonism and 5-lipoxygenase (LOX-5) inhibition by the extracts. A polyethylene oxide (PEO)-based gel composition with the M. chamomilla extracts was proposed for preparing a novel 3D-printed dosage form for oral administration. These 3D-printed extract preparations can be used, for example, in dietary supplement applications.

A 'double-edged' role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs.

We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic, and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when the light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of presumed BLA input, and decreased BLA-driven feedforward inhibition of amygdala output neurons. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.

Anticancer, anti-inflammatory and analgesic activities of aminoalcohol-based quinoxaline small molecules.

PURPOSE: Bioactive molecules are relevant to fight cancer and associated conditions. Quinoxaline is a privileged N-heterocycle, notably as anticancer agents. Herein, we report the evaluation of the quinoxaline derivatives DEQX and OAQX as anticancer agents, as well as in function of their anti-inflammatory and analgesic activities. METHODS: Quinoxalines were synthesized and tested as anticancer agents based on cell viability and Annexin V-FITC apoptosis. Anti-inflammatory activity was evaluated from mouse carrageenan peritonitis and levels of interleukin (IL)-1ß and tumor necrosis factor (TNF)-alfa for enzyme-linked immunosorbent assay. Hot-plate and acetic acid-induced writing test were employed to investigate analgesia. RESULTS: Both reduced the Ht-29 cell viability in a dependent-concentration manner (p < 0.001). Total apoptosis was detected for cells treated with 12.5 and 25 µg/mL of both the compounds for 24 and 48 h (all doses, p < 0.0001). DEQX (all doses, p < 0.01) and OAQX (all doses, p < 0.001) acted in leukocyte migration and decreased the IL-1ß and TNF-ß levels (p < 0.05). DEQX (all doses, p < 0.05) and OAQX (5mg/kg, p < 0.001) showed peripheral analgesic effect. CONCLUSIONS: In-vitro and in-vivo results suggest that these quinoxalines are promising for application in pharmacological area due to their anticancer, anti-inflammatory, and peripheric analgesia.

The analgesic effects of botulinum neurotoxin by modulating pain-related receptors; A literature review.

Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, have been used for the treatment of various central and peripheral neurological conditions. Recent studies have suggested that BoNTs may also have a beneficial effect on pain conditions. It has been hypothesized that one of the mechanisms underlying BoNTs' analgesic effects is the inhibition of pain-related receptors' transmission to the neuronal cell membrane. BoNT application disrupts the integration of synaptic vesicles with the cellular membrane, which is responsible for transporting various receptors, including pain receptors such as TRP channels, calcium channels, sodium channels, purinergic receptors, neurokinin-1 receptors, and glutamate receptors. BoNT also modulates the opioidergic system and the GABAergic system, both of which are involved in the pain process. Understanding the cellular and molecular mechanisms underlying these effects can provide valuable insights for the development of novel therapeutic approaches for pain management. This review aims to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions by inhibiting the transmission of pain-related receptors.

Changes in the analgesic mechanism of oxytocin can contribute to hyperalgesia in Parkinson's disease model rats.

Pain is a major non-motor symptom of Parkinson's disease (PD). Alterations in the descending pain inhibitory system (DPIS) have been reported to trigger hyperalgesia in PD patients. However, the underlying mechanisms remain unclear. In the current study, dopaminergic nigrostriatal lesions were induced in rats by injecting 6-hydroxydopamine (6-OHDA) into their medial forebrain bundle. The neural mechanisms underlying changes in nociception in the orofacial region of 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad. The 6-OHDA-lesioned rats were seen to exhibit increased frequency of face-rubbing and more c-Fos immunoreactive (c-Fos-IR) cells in the trigeminal spinal subnucleus caudalis (Vc), confirming hyperalgesia. Examination of the number of c-Fos-IR cells in the DPIS nuclei [including the midbrain ventrolateral periaqueductal gray, the locus coeruleus, the nucleus raphe magnus, and paraventricular nucleus (PVN)] showed that 6-OHDA-lesioned rats exhibited a significantly lower number of c-Fos-IR cells in the magnocellular division of the PVN (mPVN) after formalin injection compared to sham-operated rats. Moreover, the 6-OHDA-lesioned rats also exhibited significantly lower plasma oxytocin (OT) concentration and percentage of oxytocin-immunoreactive (OT-IR) neurons expressing c-Fos protein in the mPVN and dorsal parvocellular division of the PVN (dpPVN), which secrete the analgesic hormone OT upon activation by nociceptive stimuli, when compared to the sham-operated rats. The effect of OT on hyperalgesia in 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad after intracisternal administration of OT, and the findings showed a decrease in the frequency of face rubbing and the number of c-Fos-IR cells in the Vc. In conclusion, these findings confirm presence of hyperalgesia in PD rats, potentially due to suppression of the analgesic effects of OT originating from the PVN.

Molecular Transformers: Adaptive Multitarget Ligands for Esterase-Induced Transition from Analgesics to Anesthetics.

Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1.8 (Nav1.8) in the peripheral nervous system (PNS) for analgesia, and later the γ-aminobutyric acid subtype A receptor (GABAA) in the central nervous system (CNS) for general anesthesia. Our findings confirm KGP-25's dual efficacy in cellular and animal models, effectively reducing opioid-related side effects. This study validates the molecular transformer approach in drug design and highlights its potential to overcome the limitations of conventional MTDLs, paving new avenues in innovative therapeutic strategies.

Recent advances in small molecule Nav 1.7 inhibitors for cancer pain management.

The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs.

Repurposing of the analgesic Neurotropin for MASLD/MASH treatment.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased in recent decades. Approximately 25% of patients with MASLD progress to metabolic dysfunction-associated steatohepatitis, which is characterized by hepatic steatosis plus hepatocyte damage, inflammation, and fibrosis. We previously reported that Neurotropin (NTP), a drug used for relieving pain in Japan and China, inhibits lipid accumulation in hepatocytes by preventing mitochondrial dysfunction. We hypothesized that inhibiting hepatic steatosis and inflammation by NTP can be an effective strategy for treating MASLD and tested this hypothesis in a MASLD mouse model. METHODS: Six-week-old C57BL/6NJ male mice were fed a normal diet and normal drinking water or a high-fat diet with high fructose/glucose water for 12 weeks. During the last 6 weeks, the mice were also given high-dose NTP, low-dose NTP, or control treatment. Histologic, biochemical, and functional tests were conducted. MitoPlex, a new proteomic platform, was used to measure mitochondrial proteins, as mitochondrial dysfunction was previously reported to be associated with MASLD progression. RESULTS: NTP inhibited the development of hepatic steatosis, injury, inflammation, and fibrosis induced by feeding a high-fat diet plus high fructose/glucose in drinking water. NTP also inhibited HSC activation. MitoPlex analysis revealed that NTP upregulated the expression of mitochondrial proteins related to oxidative phosphorylation, the tricarboxylic acid cycle, mitochondrial dynamics, and fatty acid transport. CONCLUSIONS: Our results indicate that NTP prevents the development of hepatic steatosis, injury, and inflammation by preserving mitochondrial function in the liver and inhibits liver fibrosis by suppressing HSC activation. Thus, repurposing NTP may be a beneficial option for treating MASLD/metabolic dysfunction-associated steatohepatitis.

A novel cinnamic and caffeic acid-conjugated peptide analogs with anticonvulsant and analgesic potency: Comparative analyses of trans/cis isomers.

The novel cinnamic acid (CA) (H4-CA, H5-CA, and H7-CA) and caffeic acid (KA) (H4-KA, H5-KA, and H7-KA) hemorphin analogs have recently been synthesized and their trans isomers have been tested for antiseizure and antinociceptive activity. In the present study, the cis forms of these compounds were tested and compared with their trans isomers in seizure and nociception tests in mice. The cis-H5-CA and H7-CA compounds showed efficacy against psychomotor seizures, whereas the trans isomers were ineffective. Both the cis and trans KA isomers were ineffective in the 6-Hz test. In the maximal electroshock (MES) test, the cis isomers showed superior antiseizure activity to the trans forms of CA and KA conjugates, respectively. The suppression of seizure propagation by cis-H5-CA and the cis-H5-KA was reversed by a kappa opioid receptor (KOR) antagonist. Naloxone and naltrindole were not effective. The cis-isomers of CA conjugates and cis-H7-KA produced significantly stronger antinociceptive effects than their trans-isomers. The cis-H5-CA antinociception was blocked by naloxone in the acute phase and by naloxone and KOR antagonists in the inflammatory phase of the formalin test. The antinociception of the KA conjugates was not abolished by opioid receptor blockade. None of the tested conjugates affected the thermal nociceptive threshold. The results of the docking analysis also suggest a model-specific mechanism related to the activity of the cis-isomers of CA and KA conjugates in relation to opioid receptors. Our findings pave the way for the further development of novel opioid-related antiseizure and antinociceptive therapeutics.

Placebo treatment affects brain systems related to affective and cognitive processes, but not nociceptive pain.

Drug treatments for pain often do not outperform placebo, and a better understanding of placebo mechanisms is needed to improve treatment development and clinical practice. In a large-scale fMRI study (N = 392) with pre-registered analyses, we tested whether placebo analgesic treatment modulates nociceptive processes, and whether its effects generalize from conditioned to unconditioned pain modalities. Placebo treatment caused robust analgesia in conditioned thermal pain that generalized to unconditioned mechanical pain. However, placebo did not decrease pain-related fMRI activity in brain measures linked to nociceptive pain, including the Neurologic Pain Signature (NPS) and spinothalamic pathway regions, with strong support for null effects in Bayes Factor analyses. In addition, surprisingly, placebo increased activity in some spinothalamic regions for unconditioned mechanical pain. In contrast, placebo reduced activity in a neuromarker associated with higher-level contributions to pain, the Stimulus Intensity Independent Pain Signature (SIIPS), and affected activity in brain regions related to motivation and value, in both pain modalities. Individual differences in behavioral analgesia were correlated with neural changes in both modalities. Our results indicate that cognitive and affective processes primarily drive placebo analgesia, and show the potential of neuromarkers for separating treatment influences on nociception from influences on evaluative processes.