Opioid Mechanisms Research Articles

Molecular Sex Differences and Clinical Gender Efficacy in Opioid Use Disorders: From Pain Management to Addiction.

Opioids have been utilized for both medical and recreational purposes since their discovery. Primarily recognized for their analgesic properties, they are also associated with the development of tolerance and dependence, contributing to a significant public health concern worldwide. Sex differences in opioid use disorder reveal that while men historically exhibit higher rates of abuse, women may develop dependence more quickly and are more susceptible to the addictive nature of opioids. This narrative review explores sex differences in opioid response in both clinical and experimental models, focusing on opioid receptor mechanisms, pain modulation, and hormonal influences. Additionally, it discusses the complexities of opioid addiction and withdrawal, highlighting sex-specific responses and the role of opioid replacement therapies. Diverse experimental outcomes, together with observational data, underscore the need for further research into sex-specific opioid biological mechanisms in a wider context, including demographic, cultural, and health-related factors. A comprehensive understanding of these complexities holds the potential to enhance personalized opioid therapies.

Gene polymorphism impact on opioid analgesic usage.

Acute pain, moderate-to-severe cancer pain, and persistent malignant pain are all frequently treated with opioids. It is regarded as one of the main tenets of analgesic treatment. The relationship between human opioid sensitivity and genetic polymorphism differences has received little attention up to this point in research. Nonetheless, there is mounting proof that pharmacogenomic diversity could affect how each person reacts to opioids. Finding out how gene polymorphism affects analgesic use is the aim of this investigation, particularly opioids. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed in the preparation of the systematic review approach used in this work. Oxycodone, fentanyl, raclopride, tramadol, ketorolac, morphine, ropivacaine, levobupivacaine, subfentanyl, remifentanil, and nortriptyline were the opioid medications used in the study, which was based on 13 publications. From those articles, we reviewed the impact of gene polymorphism on pain management and drug pharmacokinetics. Based on this systematic review, we concluded that gene polymorphism of gene affects analgesic, specifically opioid mechanisms.

Network mechanism of opioids in treating abdominal pain caused by T-cell lymphoma

Objective: To investigate the therapeutic mechanism of opioids in abdominal pain caused by T-cell lymphoma with a combination of network pharmacology and bioinformatics analysis. Methods: Initially, we collected T-cell lymphoma, abdominal pain, and opioid-related target genes from the Genecards database. The STRING database was then utilized to construct a protein-protein interaction (PPI) network and drug-disease-hub gene-signal pathway diagram was generated using Cytoscape. Furthermore, GO and KEGG enrichment analyses were performed using the bioinformatics website. To validate the results, the predictive hub genes were validated by download data from GEO database, which had been visualized by heatmap and histogram by using R, SPSS, and GraphPad. Results: There were 857 identified cross-targets. PPI revealed 9 hub targets. GO and KEGG analysis focused on PI3K/AKT, MAPK signaling factors, and their interactions. GEO data analysis using SPSS showed upregulation of SRC, MAPK1, HRAS, and AKT1 in tumor tissue. Additionally, SPSS univariate analysis revealed statistical significance in SRC, STAT3, AKT1, and TP53. Conclusions: This study confirms the effectiveness of opioids in preclinical studies on abdominal pain caused by T-cell lymphoma, which is associated with 10 genes. Besides, the involved function and signal pathway is associated with SRC, STAT3, AKT1, and TP53. These findings may contribute to the mechanism explanation of abdominal pain in T-cell lymphoma treated with opioids.

Dexamethasone attenuates neuropathic pain through spinal microglial expression of dynorphin A via the cAMP/PKA/p38 MAPK/CREB signaling pathway

This study aimed to elucidate the opioid mechanisms underlying dexamethasone-induced pain antihypersensitive effects in neuropathic rats. Dexamethasone (subcutaneous and intrathecal) and membrane-impermeable Dex-BSA (intrathecal) administration dose-dependently inhibited mechanical allodynia and thermal hyperalgesia in neuropathic rats. Dexamethasone and Dex-BSA treatments increased expression of dynorphin A in the spinal cords and primary cultured microglia. Dexamethasone specifically enhanced dynorphin A expression in microglia but not astrocytes or neurons. Intrathecal injection of the microglial metabolic inhibitor minocycline blocked dexamethasone-stimulated spinal dynorphin A expression; intrathecal minocycline, the glucocorticoid receptor antagonist Dex-21-mesylate, dynorphin A antiserum, and κ-opioid receptor antagonist GNTI completely blocked dexamethasone-induced mechanical antiallodynia and thermal antihyperalgesia. Additionally, dexamethasone elevated spinal intracellular cAMP levels, leading to enhanced phosphorylation of PKA, p38 MAPK and CREB. The specific adenylate cyclase inhibitor DDA, PKA inhibitor H89, p38 MAPK inhibitor SB203580 and CREB inhibitor KG-501 completely blocked dexamethasone-induced anti-neuropathic pain and increased microglial dynorphin A exprression. In conclusion, this study reveal that dexamethasone mitigateds neuropathic pain through upregulation of dynorphin A in spinal microglia, likely involving the membrane glucocorticoid receptor/cAMP/PKA/p38 MAPK/CREB signaling pathway.

Intracerebroventricular administration of TRH Agonist, RX-77368 alleviates visceral pain induced by colorectal distension in rats

Thyrotropin-releasing hormone (TRH) acts centrally to exert pleiotropic actions independently from its endocrine function, including antinociceptive effects against somatic pain in rodents. Whether exogenous or endogenous activation of TRH signaling in the brain modulates visceral pain is unknown. Adult male Sprague-Dawley rats received an intracerebroventricular (ICV) injection of the stable TRH analog, RX-77368 (10, 30 and 100 ng/rat) or saline (5 µl) or were semi-restrained and exposed to cold (4°C) for 45 min. The visceromotor response (VMR) to graded phasic colorectal distensions (CRD) was monitored using non-invasive intracolonic pressure manometry. Naloxone (1 mg/kg) was injected subcutaneously 10 min before ICV RX-77368 or saline. Fecal pellet output was monitored for 1 h after ICV injection. RX-77368 ICV (10, 30 and 100 ng/rat) reduced significantly the VMR by 56.7%, 67.1% and 81.1% at 40 mmHg and by 30.3%, 58.9% and 87.4% at 60 mmHg respectively vs ICV saline. Naloxone reduced RX-77368 (30 and 100 ng, ICV) analgesic response by 51% and 28% at 40 mmHg and by 30% and 33% at 60 mmHg respectively, but had no effect per se. The visceral analgesia was mimicked by the acute exposure to cold. At the doses of 30 and 100 ng, ICV RX-77368 induced defecation within 30 min. These data established the antinociceptive action of RX-77368 injected ICV in a model of visceral pain induced by colonic distension through recruitment of both opioid and non-opioid dependent mechanisms.

Mechanisms of opioids and evaluation on existing therapies for addiction

Mechanisms of opioids and evaluation on existing therapies for addiction

Endogenous Opioids in the Homeostatic Regulation of Hunger, Satiety, and Hedonic Eating: Neurobiological Foundations.

This chapter (part one of a trilogy) summarizes the neurobiological foundations of endogenous opioids in the regulation of energy balance and eating behavior, dysregulation of which translates to maladaptive dietary responses in individuals with obesity and eating disorders, including anorexia, bulimia, and binge eating disorder. Knowledge of these neurobiological foundations is vital to researchers' and clinicians' understanding of pathophysiology as well as the science-based development of multidisciplinary diagnoses and treatments for obesity and eating disorders. We highlight mechanisms of endogenous opioids in both homeostatic and hedonic feeding behavior, review research on the dysregulation of food reward that plays a role in a wide array of obesity and disordered eating, and the clinical implications of neurobiological responses to food for current science-based treatments for obesity and eating disorders.

Impact of dietary changes on retinal neuronal plasticity in rodent models of physical and psychological trauma.

Blast injury has been implicated as the major cause of traumatic brain injury (TBI) and ocular system injury, in military operations in Iraq and Afghanistan. Soldiers exposed to traumatic stress also have undiagnosed, chronic vision problems. Here we hypothesize that excessive intake of ω-6 fatty acid linoleic acid (LA) and insufficiency of dietary long chain ω-3 polyunsaturated fatty acids (PUFAs, e.g., docosahexaenoic acid; DHA) would dysregulate endocannabinoid-mediated neuronal plasticity and immune response. The study objective was to determine the effect of blast-TBI and traumatic stress on retinal gene expression and assess the role of dietary deficiency of long chain ω-3 PUFAs on the vulnerability to these injury models. Linoleic acid was used as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% present in the current western diets, and these custom LA diets were also devoid of long chain ω-3 PUFAs. Animals were exposed to a simulated blast overpressure wave followed by a weight drop head-concussion to induce TBI. A Separate group of rats were subjected to traumatic stress by a forced immersion underwater. Our findings showed that blast-TBI exposure, post 14days, produced significant neuropathological changes such as axonal degeneration in the brain optic tracts from all the three diet groups, especially in rats fed the DHA-deprived 1 en% LA diet. Transcriptomic analysis showed that presence of DHA in the house chow diet prevented blast-induced disruption of neuronal plasticity by activating molecular networks like SNARE signaling, endocannabinoid pathway, and synaptic long-term depression when compared to DHA-deprived 8 en% LA diet group. Under traumatic stress, retinal synaptic function, neurovascular coupling, and opioid signaling mechanisms were dysregulated in rodents fed DHA-deficient diets (i.e., 8 en% LA and 1 en% LA), where reducing the levels of ω-6 linoleic acid from 8 en% to 1 en% was associated with increased neuronal plasticity and suppressed immune signaling. The findings of our study suggest that deprivation of long chain ω-3 PUFAs in the diet affects endocannabinoid-mediated neuronal plasticity, vascular function and inflammatory response that could influence the resistance of veterans to TBI and psychological trauma.

Nitric oxide and potassium channels but not opioid and cannabinoid receptors mediate tramadol-induced peripheral antinociception in rat model of paw pressure withdrawal.

Tramadol, an analgesic classified as an "atypical opioid", exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50µg/paw); AM251 (80µg/paw) and AM630 (100µg/paw) as the selective antagonists for types 1 and 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24µg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ, and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol's effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol's antinociception effect. Notably, glibenclamide blocked tramadol's antinociception in a dose-dependent manner. These findings suggest that tramadol's peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.

Endomorphin-2 analogs with C-terminal esterification display potent antinociceptive effects in the formalin pain test in mice

Previously, we have investigated three C-terminal esterified endomorphin-2 (EM-2) analogs EM-2-Me, EM-2-Et and EM-2-Bu with methyl, ethyl and tert-butyl ester modifications, respectively. These analogs produced significant antinociception in acute pain at the spinal and supraspinal levels, with reduced tolerance and gastrointestinal side effects. The present study was undertaken to determine the analgesic effects and opioid mechanisms of these three analogs in the formalin pain test. Our results demonstrated that intracerebroventricular (i.c.v.) administration of 0.67–20 nmol EM-2 analogs EM-2-Me, EM-2-Et and EM-2-Bu produced dose-dependent antinociceptive effects in both phase Ⅰ and phase Ⅱ of formalin pain. EM-2-Me and EM-2-Bu displayed more potent antinociception than morphine. Especially, EM-2-Bu exhibited the highest antinociception in phase Ⅱ of formalin pain, with the ED50 value being 2.1 nmol. Naloxone (80 nmol, i.c.v.) completely antagonized the antinociceptive effects of EM-2-Me, EM-2-Et and EM-2-Bu (20 nmol, i.c.v.) in both phase I and phase Ⅱ of formalin pain, suggesting a central opioid mechanism. Nevertheless, the antinociception induced by EM-2-Me might be involved in the release of dynorphin A, which subsequently acted on κ- opioid receptor. EM-2-Bu produced the antinociception probably by the direct activation of both μ- and δ-opioid receptors. EM-2-Me, EM-2-Et and EM-2-Bu also produced significant analgesic effects after peripheral administration, and the central opioid receptors were involved. Furthermore, EM-2-Bu had no influence on the locomotor activity after i.c.v. injection. The present investigation demonstrated that C-terminal esterified modifications of EM-2 will be beneficial for developing novel therapeutics in formalin pain.

Antidrug effects of GTS201 dipeptide, an imitation of the second bird BDNF, in morphine-addicted rats

BACKGROUND: The V.V. Zakusov Research Institute of Pharmacology developed hybrid digital sensors for the first, second, and fourth BDNF patches (GSB-214, GTSB-201, and GSB-106, respectively). When tested in vitro, on an oxidative stress model, in the culture of hippocampal neurons NT-22, the compound GTS201 (hexamethylenediamide bis-hexanoyl-seryl-lys), a simulator of the 2nd series of BDNF, activates the TrkB spy receptor and MAPK/Erk kinase pathway but does not affect the PI3K/Akt signature pathway and has neuroprotective activity similar to BDNF.
 AIM: To study the effect of GTS-201 dipeptide on the behavior of laboratory white rats during the formation of their dependency state and morphine withdrawal syndrome.
 MATERIALS AND METHODS: Morphine dependence in rats was developed due to administration of morphine in a doses escalation manner ranging from 10 to 20 mg/kg twice daily at 8-h intervals for 5 days. GTS-201 was given in 1- or 5-mg/kg doses for once in 30 minutes before morphine on the 5th day of the experiment or daily (in one of the groups) for 5 days in the morning 30 minutes before morphine administration. On the 5th day of the experiment, animals were tested for the presence of specific signs of morphine withdrawal syndrome in an open field for 5 minutes. Four experimental groups were formed: group 1 morphine hr. + naloxone (active control group); group 2 morphine hr. + GTS-201 (1) + naloxone; group 3 morphine hr. + GTS-201 (5) + naloxone; and group 4 morphine hr. + GTS-201 (1 5) + naloxone. Designations: hr. morphine administration within 5 days; (1) and (5) doses of substances in mg/kg, (1 5) chronic administration of the peptide for 5 days.
 RESULTS: When studying the effect of GTS-201 dipeptide on behavioral, somatic, and neurological markers of animal behavior after morphine withdrawal, significant changes in the severity of individual signs of withdrawal syndrome were noted. Manifestations of diarrhea were significantly decreased in all groups of animals injected with the peptide. In animals from group 3, morphine hr. + GTS201 (5) + naloxone showed the maximum effect: diarrhea was decreased by 71.0% (p 0.001), convulsions were decreased by 83.3 % (p 0.05), running was decreased by 71.4% (p 0.01), and vocalization was decreased by 62.5% (p 0.05). GTS-201, administered at a dose of 1 mg/kg once, eliminated the appearance of escape attempts in group 2, but the peptide at the same dose completely blocked convulsive reactions in rats in group 4. Despite significant changes in individual indicators, the total index (of morphine withdrawal syndrome for groups chronically injected with morphine) did not change statistically significantly compared with group 1 of active control. In the control group, its value in points was 7.3 0.36 (100%), whereas in groups 24, it ranged from 6.2 (84.9%) to 6.5 (89.0%; p 0.05).
 CONCLUSIONS: It is assumed that the antiaddictive dipeptide activity of GTS-201 is mediated by activation of these receptors and markers/the Erk-kinase signaling pathway, which does not exclude the involvement of opioid receptor mechanisms in the implementation of the observed behavioral phenomena.

The oral administration of Lotus corniculatus L. attenuates acute and chronic pain models in male rats

Ethnopharmacological relevanceLotus corniculatus L. (Fabaceae) traditionally used in Persian folk medicine to heal peritoneal inflammation and back pain. Aim of the studyTo explore the antinociceptive (acute pain) and anti-neuropathic (chronic pain) activities of Lotus corniculatus leaves essential oil (LCEO) in addition to uncovering the possible mechanisms of antinociception. Materials and methodsLCEO as well as the pure oleanolic acid (OA) compound, were assayed for their effects on acute (formalin induced paw licking test or FIPT) and chronic (cervical contusion injury models on the fifth cervical vertebra or CCS; 14-day intervals) pain. The possible involvements of NO-cGMP-K+ channel, TRPV, dopamine, cannabinoid, PPAR, adrenergic, and opioid mechanisms in the antinociceptive activity of LCEO have studied by formalin test. The levels of p53 and inflammatory markers were measured using a streptavidin biotin immune peroxidase complex and ELISA methods, respectively. ResultsThe LCEO and OA exerted antinociceptive activity in the first-phase of FIPT. Pretreatment with antagonists of TRPV1, dopamine D2, cannabinoid type1 and 2, and NO-cGMP-K+ channel blockers (glibenclamide, L-NAME and methylene blue) attenuated the antinociceptive effect of LCEO in FIPT. In addition, LCEO and OA meaningfully reduced hyperalgesia (days 6–14) and mechanical allodynia (days 2–14) in the CCS model. LCEO suppressed the apoptotic marker (p53) in CCS model and also ameliorated IL-2, TNF-α, and IL-1 in the spinal cord. ConclusionFinally, LCEO inhibited acute (possibly via the modulation of opioid, TRPV, dopamine, cannabinoid mechanisms as well as NO-cGMP-K+ channel) and chronic pain (via suppressing apoptotic and inflammatory markers) in male rats. The results also suggest that OA has analgesic activity against acute and chronic pain conditions.

Effects of oral morphine on experimentally evoked itch and pain: a randomized, double-blind, placebo-controlled trial.

Pain and itch share similar neuronal networks; hence, it is difficult to explain why opioids can relieve painbut provoke itching. The present human volunteer study aimed to investigate the similarities and differences in responses to experimentally provoked pain and itching to explore the underlying fundamental mechanisms. Twenty-four healthy volunteers were enrolled in this single-center, randomized, double-blind, placebo-controlled, parallel-group trial. Three volar forearms and two mandibular areas were marked, and participants randomly received morphine (20 mg) or identical placebo tablets. Heat, cold, and pressure pain thresholds, and vasomotor responses were assessed at baseline and after oral morphine administration. Itch provocations were induced by intradermal application of 1 % histamine or a topical cowhage (non-histaminergic itch) to a marked area of theskin. The participants were subsequently asked to rate their itching and pain intensities. The assessments were repeated for all marked areas. Morphine caused analgesia, as assessed by the significant modulation of cold and pressure pain thresholds (p<0.05). There were no significant differences in histaminergic or non-histaminergic itch or pain intensity between the morphine and placebo groups. Superficial blood perfusion (vasomotor response) following histamine provocation wassignificantly increased by morphine (p<0.05) in both areas. No correlation was found between the provoked itch intensity and analgesic efficacy in any area or group. Oral administration of morphine caused analgesia without modulating itch intensities but increased neurogenic inflammation in response to histamine, suggesting that different opioid mechanisms in histaminergic and non-histaminergic neurons evoke neurogenic inflammation.

Attitudes and Practices Surrounding Opioid Prescriptions following Open Reduction Internal Fixation of Distal Radius and Ankle Fractures: A Survey of the Canadian Orthopaedic Association Membership.

The past two decades have seen a significant increase in consequences associated with nonmedical misuse of prescription opioids, such as addiction and unintentional overdose deaths. This study aimed to use an electronic survey to assess attitudes and opioid-prescribing practices of Canadian orthopaedic surgeons and trainees following open reduction internal fixation (ORIF) of distal radius and ankle fractures. This study was the first to assess these factors following ORIF of distal radius and ankle fractures using a survey design. A 40-item survey was developed focusing on four themes: respondent demographics, opioid-prescribing practice, patients with substance use disorders, and drug diversion. The survey was distributed among members of the Canadian Orthopaedic Association. Descriptive statistics were used to summarize respondent demographics and outcomes of interest. A Chi-square test was used to determine if proportion of opioid prescriptions between attending surgeons and surgeons in training was equal. 191 surveys were completed. Most respondents prescribed 10-40 tabs of immediate-release opioids, though this number varied considerably. While most respondents believed patients consumed only 40-80% of the prescribed opioids (73.6%), only 28.7% of respondents counselled patients on safe storage/disposal of leftover opioids. 30.5% of respondents felt confident in their knowledge of opioid use and mechanisms of addiction. Most respondents desired further education on topics such as procedure-based opioid-prescribing protocols (74.2%), alternative pain management strategies (69.7%), and mechanisms of opioid addiction (49.0%). The principle finding of this study is the lack of a standardized approach to postoperative prescribing in distal radius and ankle fractures, illustrated by the wide range in number of opioids prescribed by Canadian orthopaedic surgeons. Our data suggest a trend towards overprescription among respondents following distal radius and ankle ORIF. Future studies should aim to rationalize interventions targeted at reducing postoperative opioid prescribing for common orthopaedic trauma procedures.

Exogenous histamine and H 2 receptor activation and H 3 receptor inhibition in nucleus accumbens modulate formalin-induced orofacial nociception through opioid receptors.

It has been demonstrated that the nucleus accumbens (NAc) plays an important role in modulation of nociception due to its extensive connections with different regions of the brain. In addition, this nucleus receives histaminergic projections from tuberomammillary nucleus. Considering the role of the central histaminergic system in nociception, the effect of histamine and its H 2 and H 3 receptors agonist and antagonist microinjections into the NAc on orofacial formalin nociception was investigated. In male Wistar rats, using stereotaxic surgery, two guide cannulas were bilaterally implanted into the right and left sides of the NAc. Diluted formalin solution (1.5%, 50 µl) injection into the vibrissa pad led to orofacial nociception. Immediately after injection, face rubbing was observed at 3-min blocks for 45 min. Orofacial formalin nociception was characterized by a biphasic nociceptive response (first phase: 0-3 min and second phase: 15-33 min). Microinjections of histamine (0.5 and 1 μg/site), dimaprit (1 μg/site, H 2 receptor agonist) and thioperamide (2 μg/site, H 3 receptor antagonist) attenuated both phases of formalin orofacial nociception. Prior microinjection of famotidine (2 μg/site) inhibited the antinociceptive effects of dimaprit (1 μg/site). Furthermore, comicroinjection of thioperamide (2 μg/site) and immepip (1 μg/site) prevented thioperamide (2 μg/site)-induced antinociception. Naloxone (2 μg/site) also prevented histamine, dimaprit- and thioperamide-induced antinociception. The results of this study demonstrate that at the level of the NAc, histamine and its H 2 and H 3 receptors are probably involved in the modulation of orofacial nociception with an opioid system-dependent mechanism.

Analgesic Effects of Vagus Nerve Stimulation on Visceral Hypersensitivity: A Direct Comparison Between Invasive and Noninvasive Methods in Rats

ObjectivesThe aims of this study were to investigate analgesic effects of vagus nerve stimulation (VNS) on visceral hypersensitivity (VH) in a rodent model of functional dyspepsia (FD) and to compare invasive VNS with noninvasive auricular VNS (aVNS). Materials and MethodsEighteen ten-day-old male rats were gavaged with 0.1% iodoacetamide (IA) or 2% sucrose solution for six days. After eight weeks, IA-treated rats were implanted with electrodes for VNS or aVNS (n = 6 per group). Different parameters, varying in frequency and stimulation duty cycle, were tested to find the best parameter based on the improvement of VH assessed by electromyogram (EMG) during gastric distension. ResultsCompared with sucrose-treated rats, visceral sensitivity was increased significantly in IA-treated “FD” rats and ameliorated remarkably by VNS (at 40, 60, and 80 mm Hg; p ≤ 0.02, respectively) and aVNS (at 60 and 80 mm Hg; p ≤ 0.05, respectively) with the parameter of 100 Hz and 20% duty cycle. There was no significant difference in area under the curve of EMG responses between VNS and aVNS (at 60 and 80 mm Hg, both p > 0.05). Spectral analysis of heart rate variability revealed a significant enhancement in vagal efferent activity while applying VNS/aVNS compared with sham stimulation (p < 0.01). In the presence of atropine, no significant differences were noted in EMG after VNS/aVNS. Naloxone blocked the analgesic effects of VNS/aVNS. ConclusionsVNS/aVNS with optimized parameter elicits ameliorative effects on VH, mediated by autonomic and opioid mechanisms. aVNS is as effective as direct VNS and has great potential for treating visceral pain in patients with FD.

N-palmitoylethanolamide synergizes the antinociception of morphine and gabapentin in the formalin test in mice.

The antinociceptive pharmacological interaction between N-palmitoylethanolamide (PEA) and morphine (MOR), as well as gabapentin (GBP), was investigated to obtain synergistic antinociception at doses where side effects were minimal. In addition, the possible antinociceptive mechanism of PEA + MOR or PEA + GBP combinations was explored. Individual dose-response curves (DRCs) of PEA, MOR and GBP were evaluated in female mice in which intraplantar nociception was induced with 2% formalin. Isobolographic method was used to detect the pharmacological interaction in the combination of PEA + MOR or PEA + GBP. The ED50 was calculated from the DRC; the order of potency was MOR > PEA > GBP. The isobolographic analysis was obtained at a 1:1 ratio to determine the pharmacological interaction. The experimental values of flinching (PEA + MOR, Zexp = 2.72 ± 0.2 μg/paw and PEA + GBP Zexp = 2.77 ± 0.19 μg/paw) were significantly lower than those calculated theoretically (PEA + MOR Zadd = 7.78 ± 1.07 and PEA + GBP Zadd = 24.05 ± 1.91 μg/paw), resulting in synergistic antinociception. Pretreatment with GW6471 and naloxone demonstrated that peroxisome proliferator-activated receptor alpha (PPARα) and opioid receptors are involved in both interactions. These results suggest that MOR and GBP synergistically enhance PEA-induced antinociception through PPARα and opioid receptor mechanisms. Furthermore, the results suggest that combinations containing PEA with MOR or GBP could be of interest in aiding the treatment of inflammatory pain.

Opioid Mechanisms and the Treatment of Depression.

Opioid receptors are widely expressed in the brain, and the opioid system has a key role in modulating mood, reward processing and stress responsivity. There is mounting evidence that the endogenous opioid system may be dysregulated in depression and that drug treatments targeting mu, delta and kappa opioid receptors may show antidepressant potential. The mechanisms underlying the therapeutic effects of opioid system engagement are complex and likely multi-factorial. This chapter explores various pathways through which the modulation of the opioid system may influence depression. These include impacts on monoaminergic systems, the regulation of stress and the hypothalamic-pituitary-adrenal axis, the immune system and inflammation, brain-derived neurotrophic factors, neurogenesis and neuroplasticity, social pain and social reward, as well as expectancy and placebo effects. A greater understanding of the diverse mechanisms through which opioid system modulation may improve depressive symptoms could ultimately aid in the development of safe and effective alternative treatments for individuals with difficult-to-treat depression.

Topical Calendula officinalis L. inhibits inflammatory pain through antioxidant, anti-inflammatory and peripheral opioid mechanisms

ObjectiveThe present study evaluated the antinociceptive activity of Calendula officinalis L. (Ca) cream on inflammatory hypernociception. MethodsCreams with different Ca concentrations were tested for their ability to ameliorate pain-related behavior and edema in rats using formalin test, carrageenan (Cg)-induced acute inflammation model, bradykinin (BK)-induced acute inflammation model, and complete Freund’s adjuvant (CFA)-induced chronic inflammation model. Using the formalin test, we also examined the implication of peripheral opioid receptors in the antinociceptive mechanisms of Ca cream, by means of Q-naloxone, a peripherally acting nonselective opioid antagonist. Furthermore, the effects of Ca cream compared with diclofenac on BK-induced edema were examined when the kininase II in tissue was preserved or inhibited by captopril. The local production of redox biomarkers in formalin model, tumor necrosis factor-α (TNF-α) in Cg model and histopathological changes in CFA model were also evaluated. ResultsA single application of Ca cream at a dose of 10% or 30% (w/w) decreased the formalin-induced licking/biting behavior during both phases of this test in a Q-naloxone-sensitive manner. This effect was associated with the reduction of oxidative stress in the injured paw and the edema associated with the later phase of formalin-induced pain. A single application of Ca cream (10% or 30%) reduced paw edema and thermal hypernociception in Cg-induced acute inflammation, corresponding with a local decrease in TNF-α. Ca cream also inhibited BK-induced spontaneous nociceptive behavior and paw inflammation in both paradigms studied. Repeated applications of Ca cream also decreased CFA-induced chronic inflammation, mechanical hypernociception and histopathological changes in the paw. ConclusionThese results reveal the topical antinociceptive and antiedematogenic effects of Ca cream. A modulatory action on peripheral opioid receptors associated with its antioxidant mechanism may be involved, at least in part, in its analgesic effects. These findings may have an impact on the clinical management of painful inflammatory diseases.

Postsurgical Latent Pain Sensitization Is Driven by Descending Serotonergic Facilitation and Masked by µ-Opioid Receptor Constitutive Activity in the Rostral Ventromedial Medulla.

Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MORCA) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3-4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity. We first tested the hypothesis that LS extends to serotonergic neurons in the rostral ventral medulla (RVM) that convey pronociceptive input to the spinal cord. We report that in male and female mice, hypersensitivity was accompanied by increased Fos expression in serotonergic neurons of the RVM, abolished on chemogenetic inhibition of RVM 5-HT neurons, and blocked by intrathecal injection of the 5-HT3R antagonist ondansetron; the 5-HT2AR antagonist MDL-11 939 had no effect. Second, to test for MORCA, we microinjected the MOR inverse agonist d-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) and/or neutral opioid receptor antagonist 6β-naltrexol. Intra-RVM CTAP produced mechanical hypersensitivity at both hindpaws; 6β-naltrexol had no effect by itself, but blocked CTAP-induced hypersensitivity. This indicates that MORCA, rather than an opioid ligand-dependent mechanism, maintains LS in remission. We conclude that incision establishes LS in descending RVM 5-HT neurons that drives pronociceptive 5-HT3R signaling in the dorsal horn, and this LS is tonically opposed by MORCA in the RVM. The 5-HT3 receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.SIGNIFICANCE STATEMENT Surgery leads to latent pain sensitization and a compensatory state of endogenous pain control that is maintained long after tissue healing. Here, we show that either chemogenetic inhibition of serotonergic neuron activity in the RVM or pharmacological inhibition of 5-HT3 receptor signaling at the spinal cord blocks behavioral signs of postsurgical latent sensitization. We conclude that MORCA in the RVM opposes descending serotonergic facilitation of LS and that the 5-HT3 receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.