Evaluation of antinociceptive activity of Ilex dipyrena Wall. in mice.

BACKGROUND: In order to find a new natural resource for pain-relief, the analgesic effects of Ilex dipyrena crude extract, fractions, and subfractions were evaluated in in-vivo mouse models with possible mechanism of action. METHODS: Analgesic effects of crude extract (100 and 200 mg/kg body weight), fractions and subfractions (75 mg/kg body weight) were screened using heat-induced (tail-immersion and hot plate test) and chemical-induced (formalin and acetic acid) nociception models in mice. The samples were also tested for the elucidation of a possible mechanism through opioidergic and GABAergic systems. RESULTS: The administration of crude extract, fractions and subfractions produced analgesic responses in acetic acid, formalin, tail immersion, and hot plate model for pain similar to those obtained with the standard. Naloxone antagonized the antinociceptive effects of the tested samples, whereas bicuculline showed partial inhibition. Considering the analgesic response, crude extract, fractions, and subfractions demonstrated promising inhibitory activity against all test models for pain, which was further supported by the possible involvement of opioidergic and GABAergic systems. CONCLUSION: The results suggest that this plant may be useful in the development of new analgesic drugs. Further research with regard to the isolation of bioactive compounds is required to verify these findings.

Lyophilized Kratom Tea as a Therapeutic Option for Opioid Dependence.

BACKGROUND: Made as a tea, the Thai traditional drug "kratom" reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects. METHODS: Lyophilized kratom tea (LKT) was evaluated in C57BL/6J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 °C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA. RESULTS: Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice. CONCLUSIONS: The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.

Selenium Nanoparticles Induce Potent Protective Immune Responses against Vibrio cholerae WC Vaccine in a Mouse Model.

The aim of this study was to evaluate the efficacy of selenium nanoparticle (an immune booster) and naloxone (an opioid receptor antagonist) as a new adjuvant in increasing immune responses against killed whole-cell Vibrio cholerae in a mouse cholera model. The Se NPs were synthesized and characterized by UV-visible, DLS, and zeta potential analysis. The SEM image confirmed the uniformity of spherical morphology of nanoparticle shape with 34 nm in size. The concentration of the Se NPs was calculated as 0.654 µg/ml in the ICP method. The cytotoxic activity of Se NPs on Caco-2 cells was assessed by the MTT assay and revealed 82.05% viability of cells after 24 h exposure with 100 µg/ml of Se NPs. Female BALB/C mice were orally immunized three times on days 0, 14, and 28, and challenge experiments were performed on immunized neonates with toxigenic V. cholerae. Administration of Se NP diet led to significant increase in V. cholerae-specific IgG and IgA responses in serum and saliva and caused protective immunity and 83.3% survival in challenge experiment against 1 LD50 V. cholerae in a group receiving diet of Se NPs compared with other groups including Dukoral vaccine. The IL-4 and IL-5 were significantly increased in response to WC+daily diet of Se NPs with or without naloxone. Naloxone proved no effect on IL-4 and IL-5 increase and is proposed as null in the cytokine and antibody production process. These results reveal that daily diet of Se NPs could efficiently induce immune cell effectors in both humoral and mucosal levels.

Development of an algorithm to identify inpatient opioid-related overdoses and oversedation using electronic data.

PURPOSE: To facilitate surveillance and evaluate interventions addressing opioid-related overdoses, algorithms are needed for use in large health care databases to identify and differentiate community-occurring opioid-related overdoses from inpatient-occurring opioid-related overdose/oversedation. METHODS: Data were from Kaiser Permanente Northwest (KPNW), a large integrated health plan. We iteratively developed and evaluated an algorithm for electronically identifying inpatient overdose/oversedation in KPNW hospitals from 1 January 2008 to 31 December 2014. Chart audits assessed accuracy; data sources included administrative and clinical records. RESULTS: The best-performing algorithm used these rules: (1) Include events with opioids administered in an inpatient setting (including emergency department/urgent care) followed by naloxone administration within 275 hours of continuous inpatient stay; (2) exclude events with electroconvulsive therapy procedure codes; and (3) exclude events in which an opioid was administered prior to hospital discharge and followed by readmission with subsequent naloxone administration. Using this algorithm, we identified 870 suspect inpatient overdose/oversedation events and chart audited a random sample of 235. Of the random sample, 185 (78.7%) were deemed overdoses/oversedation, 37 (15.5%) were not, and 13 (5.5%) were possible cases. The number of hours between time of opioid and naloxone administration did not affect algorithm accuracy. When "possible" overdoses/oversedations were included with confirmed events, overall positive predictive value (PPV) was very good (PPV = 84.0%). Additionally, PPV was reasonable when evaluated specifically for hospital stays with emergency/urgent care admissions (PPV = 77.0%) and excellent for elective surgery admissions (PPV = 97.0%). CONCLUSIONS: Algorithm performance was reasonable for identifying inpatient overdose/oversedation with best performance among elective surgery patients.

Legally Lethal Kratom: A Herbal Supplement with Overdose Potential.

This case report describes an overdose on kratom, and elicits the potential dangers of overdose on the regulated dietary supplement. A young male presented to the emergency department intubated after being found unresponsive. He was found by his family to be unarousable and agonal breathing with minimal response to naloxone administered by Emergency Medical Services (EMS). Urine toxicology and blood alcohol content were negative. Physical exam was significant for tachycardia, hypotension, and pinpoint pupils with sluggish reactivity to light. Laboratory studies were significant for elevated liver enzymes, blood urea nitrogen, creatinine, lipase, amylase, troponins, and lactic acid. Family members revealed that the patient consumed kratom, which he obtained through an e-commerce business, and had consumed over 500 grams the previous day. Urine sample for kratom on day 3 tested positive with levels of more than 500 ng/dL. The patient received supportive care and, by day 10, pupillary reflexes returned to normal and he was extubated by day 14. Most of the medications/drugs labelled under herbal supplements by the U.S. Food and Drug Administration (FDA) are not regulated and can be purchased over the counter. The safety and side-effect profile of kratom is not well-studied, especially in an overdose scenario.

Treating Opioid Dependence: Pain Medicine Physiology of Tolerance and Addiction.

Inappropriate and excessive opioid prescribing practices for treatment of chronic nonmalignant pain contributed to rising rates of opioid related mortality. Effective and widely available opioid addiction treatment resources are needed to ensure successful resolution of the "opioid epidemic". This chapter outlines the basic pathophysiology of addiction as well as principles of opioid addiction management focusing on the pharmacological and nonpharmacological aspects of care. Pharmacological treatment focuses on opioid substitution therapy, with aim at prevention of opioid cravings and opioid withdrawal symptoms. Nonpharmacological treatment involves psychological and supportive approaches to addiction such as group meetings, psychological counseling, and mindfulness training.

Opioid-Independent and Opioid-Mediated Modes of Pain Modulation.

Pain is regulated endogenously through both opioid and non-opioid mechanisms. We hypothesized that two novel pain modulation tasks, one drawing on context/expectations and one using voluntary reappraisal, would show differing levels of opioid dependence. Specifically, we expected that naloxone would block context-related analgesia, whereas mental imagery-based pain reappraisal would be opioid-independent.A double-blind, placebo-controlled intravenous naloxone versus saline crossover design was used. Twenty healthy volunteers completed the two modulation tasks with acute heat stimuli calibrated to induce moderate pain. In the mental imagery task, participants imagined either a "pleasant" or a "comparison" scenario during painful heat. In the relative relief task, moderate heat stimuli coincided with visual cues eliciting relief from the expectation of intense pain, and were compared with moderate heat stimuli delivered under the expectation of non-painful warmth. Both "pleasant imagery" and "relative relief" conditions significantly improved ratings of pain intensity and pleasantness during saline treatment. Indeed, the target stimuli in both tasks, which had been calibrated to induce moderate pain, were rated as mildly pleasant. Furthermore, consistently with the main hypothesis, blocking endogenous opioid signaling with naloxone did not significantly affect imagery-induced regulation of pain intensity or pleasantness. In contrast, the relative relief-induced pain regulation (i.e., context/expectation) was blocked by naloxone. We conclude that endogenous opioid signaling is necessary for expectation-related relative relief analgesia, but not for pain reappraisal through mental imagery. These results support mental imagery as a powerful and clinically relevant strategy for regulating pain affect also in patients where endogenous opioid mechanisms might be compromised.SIGNIFICANCE STATEMENT Neurotransmitter systems in the human brain can be probed through antagonist drugs. Studies using the opioid antagonist naloxone have demonstrated that the brain relies on both opioid and non-opioid mechanisms to downregulate pain. This holds clinical relevance given altered endogenous opioid processes in many chronic pain conditions. The present study used a double-blinded, placebo-controlled naloxone blockage of endogenous opioids in healthy humans to show differential opioid involvement in two pain modulation tasks. Context/expectation-driven (relative relief-related) analgesia was blocked by naloxone. In contrast, pain reappraisal through mental imagery was intact despite opioid receptor blockade, suggesting opioid independence. These results support mental imagery as a powerful, clinically relevant strategy for regulating pain as it does not rely on a functioning opioidergic system.

Post-stroke Intranasal (+)-Naloxone Delivery Reduces Microglial Activation and Improves Behavioral Recovery from Ischemic Injury.

Ischemic stroke is the leading cause of disability, and effective therapeutic strategies are needed to promote complete recovery. Neuroinflammation plays a significant role in stroke pathophysiology, and there is limited understanding of how it affects recovery. The aim of this study was to characterize the spatiotemporal expression profile of microglial activation and whether dampening microglial/macrophage activation post-stroke facilitates the recovery. For dampening microglial/macrophage activation, we chose intranasal administration of naloxone, a drug that is already in clinical use for opioid overdose and is known to decrease microglia/macrophage activation. We characterized the temporal progression of microglia/macrophage activation following cortical ischemic injury in rat and found the peak activation in cortex 7 d post-stroke. Unexpectedly, there was a chronic expression of phagocytic cells in the thalamus associated with neuronal loss. (+)-Naloxone, an enantiomer that reduces microglial activation without antagonizing opioid receptors, was administered intranasally starting 1 d post-stroke and continuing for 7 d. (+)-Naloxone treatment decreased microglia/macrophage activation in the striatum and thalamus, promoted behavioral recovery during the 14-d monitoring period, and reduced neuronal death in the lesioned cortex and ipsilateral thalamus. Our results are the first to show that post-stroke intranasal (+)-naloxone administration promotes short-term functional recovery and reduces microglia/macrophage activation. Therefore, (+)-naloxone is a promising drug for the treatment of ischemic stroke, and further studies should be conducted.

[Temporary approval for intranasal naloxone: Setting up in a French addiction center]. / Pratique de l'ATU de cohorte de la naloxone intranasale (Nalscue®) : mise en place dans un CSAPA parisien.

Intranasal naloxone aims at preventing opioid overdose related deaths in active drug users. In France, it has been available since July 2016 through a temporary approval which requires a hospital-based pharmacy and a nominative registration of each patient. We present the characteristics of the first patients who could receive this prescription in our hospital-based addiction center and how they used naloxone during follow-up. Results favor a larger dispensing of naloxone. Patients' as well as peers' and families' education is needed.

Enhancement of Meditation Analgesia by Opioid Antagonist in Experienced Meditators.

OBJECTIVE: Studies have consistently shown that long-term meditation practice is associated with reduced pain, but the neural mechanisms by which long-term meditation practice reduces pain remain unclear. This study tested endogenous opioid involvement in meditation analgesia associated with long-term meditation practice. METHODS: Electrical pain was induced with randomized, double-blind, cross-over administration of the opioid antagonist naloxone (0.15-mg/kg bolus dose, then 0.2-mg/kg per hour infusion dose) with 32 healthy, experienced meditation practitioners and a standardized open monitoring meditation. RESULTS: Under saline, pain ratings were significantly lower during meditation (pain intensity: 6.41 ± 1.32; pain unpleasantness: 3.98 ± 2.17) than at baseline (pain intensity: 6.86 ±1.04, t(31) = 2.476, p = .019, Cohen's d = 0.46; pain unpleasantness: 4.96 ±1.75, t(31) = 3.746, p = .001, Cohen's d = 0.68), confirming the presence of meditation analgesia. Comparing saline and naloxone revealed significantly lower pain intensity (t(31) = 3.12, p = .004, d = 0.56), and pain unpleasantness (t(31) = 3.47, p = .002, d = 0.62), during meditation under naloxone (pain intensity: 5.53 ± 1.54; pain unpleasantness: 2.95 ± 1.88) than under saline (pain intensity: 6.41 ± 1.32; pain unpleasantness: 3.98 ± 2.17). Naloxone not only failed to eliminate meditation analgesia but also made meditation analgesia stronger. CONCLUSIONS: Long-term meditation practice does not rely on endogenous opioids to reduce pain. Naloxone's blockade of opioid receptors enhanced meditation analgesia; pain ratings during meditation were significantly lower under naloxone than under saline. Possible biological mechanisms by which naloxone-induced opioid receptor blockade enhances meditation analgesia are discussed.

An interesting case of opium tea toxicity.

We present an unusual cause of respiratory arrest resulting from sole ingestion of home-brewed opium tea. A 64-year-old woman was found unresponsive and in respiratory arrest by a first responder. There were no obvious signs of regular recreational drug use. On presentation to the local district general hospital, the patient was in extremis, with severe physiological and biochemical derangements. A naloxone infusion was commenced and she later made a good recovery. It was subsequently discovered that she had brewed opium tea from opium buds she had picked from a nearby commercial poppy farm, a practice she had learnt while in Afghanistan.

Experimental Research Showing the Reduction of Naloxone-Place Aversion by Oral Zinc Administration in Rats.

Previous studies showed the attenuation of both morphine-dependence and morphine-place preference by zinc. Conditioned place preference and aversion are experimental models frequently used to test the reward-stimulating, respectively the aversive effects induced by different stimuli or substances. Addictive substances usually induce place preference (exhibit reward-stimulating properties), while their antagonists determine place-avoidance (aversion). The present study aimed to assess the effect determined by zinc sulphate oral administration (2 and 4 mg/kg/day, 14 days, prior to habituation) on the place aversion induced by two naloxone doses (1.5 and 2.5 mg/kg/administration). The results show a robust, dose-dependent reduction of the aversion determined by both naloxone doses (the aversion induced by 1.5 mg/kg naloxone was reduced with 15%-the lower zinc dose and with 24%-the higher zinc dose; the aversion induced by 2.5 mg/kg naloxone was reduced with 16%-the lower zinc dose and with 29%-the higher zinc dose). This represents a new proof of the interactions between zinc and opioidergic system and a further argument for dietary zinc supplementation in patients on opioids for cancer-related chronic pain.

Trends in naloxone prescriptions prescribed after implementation of a National Academic Detailing Service in the Veterans Health Administration: A preliminary analysis.

OBJECTIVES: To evaluate the effects of the U.S. Veterans Health Administration (VA) National Academic Detailing Service alongside the Opioid Overdose Education and Naloxone Distribution (OEND) program on naloxone prescriptions prescribed from October 2014 to September 2016. METHODS: A retrospective, repeated measures cohort study was conducted to evaluate the effectiveness of a real-world application of academic detailing (AD) alongside OEND on providers' outpatient naloxone prescribing from October 2014 to September 2016. Outcome was the number of naloxone prescriptions prescribed per month per provider. During the study period, VA providers were aware of OEND, but may not have been exposed to academic detailing. Therefore, providers were categorized as exposed when the first OEND-specific academic detailing session was provided during the study period. Generalized estimating equations were used to estimate the association between exposure to academic detailing and monthly naloxone prescriptions prescribed while taking into account the correlation within each provider. Incident rate ratios with 95% CIs were reported. RESULTS: Seven hundred fifty (22.6%) of 3313 providers received at least 1 OEND-specific academic detailing visit. At 1 year, the average number of naloxone prescriptions per month was 3-times greater in AD-exposed providers compared with AD-unexposed providers (95% CI 2.0-5.3); and at 2 years, the average number of naloxone prescriptions was 7-times greater (95% CI 3.0-17.9). Moreover, the average difference in naloxone prescribing from baseline to 2 years was 7.1% greater in AD-exposed providers compared with AD-unexposed providers (95% CI 2.0%-12.5%). CONCLUSIONS: This preliminary analysis provides the first evidence that academic detailing influenced naloxone prescribing rates in a large, integrated health care system at 1 and 2 years. In addition, AD-exposed providers had a higher average difference in naloxone prescribing rate compared with AD-unexposed providers after 2 years of follow-up.

100-Hz Electroacupuncture but not 2-Hz Electroacupuncture is Preemptive Against Postincision Pain in Rats.

Preemptive analgesia involves introducing an analgesic before noxious stimulation. Electroacupuncture (EA) activates descending mechanisms that modulate nociceptive inputs into the spinal dorsal horn. This study evaluated whether preoperative EA is more effective than postoperative EA in reducing incision pain in rats. The nociceptive threshold to mechanical stimulation was utilized to examine the effects of an intraperitoneal injection of saline (0.1 mL/kg) or naloxone (1 mg/kg) on antinociception induced by a 20-minute period of 2-Hz or 100-Hz EA applied to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints before surgical incision, or 10 minutes after or 100 minutes after surgical incision of the hind paw. The extent of mechanical hyperalgesia after the incision was significantly attenuated by the application of 100-Hz EA preoperatively, but not by its application at 10 minutes or 100 minutes postoperatively. By contrast, 2-Hz EA was effective against postoperative hyperalgesia when applied 10 minutes or 100 minutes after surgery but not when it was applied preoperatively. Only the effect of 2-Hz EA applied 10 minutes after surgery was sensitive to naloxone. The present study showed for the first time that 100-Hz EA, but not 2-Hz EA, exerts a nonopioidergic preemptive effect against postincision pain in rats.

Hyperbaric oxygen treatment suppresses withdrawal signs in morphine-dependent mice.

Hyperbaric oxygen (HBO2) therapy reportedly reduces opiate withdrawal in human subjects. The purpose of this research was to determine whether HBO2 treatment could suppress physical signs of withdrawal in opiate-dependent mice. Male NIH Swiss mice were injected s.c. with morphine sulfate twice a day for 4 days, the daily dose gradually increasing from 50mg/kg on day 1 to 125mg/kg on day 4. On day 5, withdrawal was precipitated by i.p. injection of 5.0mg/kg naloxone. Mice were observed for physical withdrawal signs, including jumping, forepaw tremor, wet-dog shakes, rearing and defecation for 30min. Sixty min prior to the naloxone injection, different groups of mice received either a 30-min or 60-min HBO2 treatment at 3.5atm absolute. HBO2 treatment significantly reduced naloxone-precipitated jumping, forepaw tremor, wet-dog shakes, rearing and defecation. Based on these experimental findings, we concluded that treatment with HBO2 can suppress physical signs of withdrawal syndrome in morphine-dependent mice.

Neonatal Abstinence Syndrome: Presentation and Treatment Considerations.

This clinical case conference discusses the treatment of a pregnant woman with opioid use disorder in a comprehensive care program that includes buprenorphine pharmacotherapy. The presentation summarizes common experiences that pregnant women who receive buprenorphine pharmacotherapy face, and also what their prenatally opioid-exposed children confront in the immediate postpartum period. It describes the elements of a successful comprehensive care model and corollary neonatal abstinence syndrome treatment regimen. Expert commentary is included on issues that arise in the buprenorphine induction and maintenance throughout the prenatal and postpartum periods and in the treatment of co-occurring mental health problems during both the prenatal and postpartum periods, particularly the treatment of depression. There is also expert commentary on the care of opioid-exposed neonates, with attention to the treatment for neonatal abstinence syndrome.

Low-frequency electroacupuncture suppresses focal epilepsy and improves epilepsy-induced sleep disruptions.

BACKGROUND: The positive effects of acupuncture at Feng-Chi acupoints on treating epilepsy and insomnia have been well-documented in ancient Chinese literature. However, there is a lack of scientific evidence to elucidate the underlying mechanisms behind these effects. Our previous study demonstrated that high-frequency (100 Hz) electroacupuncture (EA) at Feng-Chi acupoints deteriorates both pilocarpine-induced focal epilepsy and sleep disruptions. This study investigated the effects of low-frequency (10 Hz) EA on epileptic activities and epilepsy-induced sleep disruptions. RESULTS: In rats, the Feng-Chi acupoint is located 3 mm away from the center of a line between the two ears. Rats received 30 min of 10 Hz EA stimuli per day before each day's dark period for three consecutive days. Our results indicated that administration of pilocarpine into the left CeA at the beginning of the dark period induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep during the consequent light period. Low-frequency (10 Hz) EA at Feng-Chi acupoints suppressed pilocarpine-induced epileptiform EEGs, and this effect was in turn blocked by naloxone (a broad-spectrum opioid receptor antagonist), but not by naloxonazine (a µ-receptor antagonist), naltrindole (a δ-receptor antagonist) and nor-binaltorphimine (a κ-receptor antagonist). Ten Hz EA enhanced NREM sleep during the dark period, and this enhancement was blocked by all of the opioid receptor antagonists. On the other hand, 10 Hz EA reversed pilocarpine-induced NREM suppression during the light period, and the EA's effect on the sleep disruption was only blocked by naloxonazine. CONCLUSIONS: These results indicate that low-frequency EA stimulation of Feng-Chi acupoints is beneficial in improving epilepsy and epilepsy-induced sleep disruptions, and that opioid receptors in the CeA mediate EA's therapeutic effects.

Hospitalist management of vaso-occlusive pain crisis in patients with sickle cell disease using a pathway of care.

BACKGROUND: Patients with sickle cell disease (SCD) suffer from intermittent vaso-occlusive pain crises (VOCs). These crises lead to frequent hospitalizations, significant morbidity, and increased mortality risk. Care pathways can enhance efficiency and quality of care. Our study sought to evaluate the development and implementation of a care pathway for patients with SCD experiencing VOCs. METHODS: The University of North Carolina (UNC) Comprehensive Sickle Cell Program provides all levels of care for a large population of patients with sickle cell anemia. All patients admitted to UNC Hospitals with SCD VOCs from January 2009 through June 2011 were evaluated. During this time period, we also assessed sequential prospective cohorts during progressive phases of developing and implementing a quality improvement and pathway of care program for this patient population in our study. The developed pathway entailed geographic localization for VOC patients, a single group of faculty physicians caring for these patients, and early use of patient-controlled analgesia (PCA) to achieve pain control. Physicians from the UNC Hospital Medicine Program were responsible for the initiatives. Cohorts were compared to a baseline historical control. Outcomes of interest included patient length of stay (LOS) in the hospital, 30-day readmission rate, need for transfusion, incidence of acute chest syndrome, use of naloxone, and use of PCA. RESULTS: Compared with an historical baseline cohort, the development and implementation of a VOC care pathway for patients with SCD led to reduction in average hospital LOS by 1.44 days (P < 0.05) and an increase in use of PCAs (P < 0.05). Patient readmission rates, number of transfusions, incidence of acute chest syndrome, and use of naloxone did not significantly change. CONCLUSIONS: Hospitalist-led management of patients with SCD VOCs using a care pathway that emphasizes early, aggressive PCA-based pain control is associated with reduced hospital LOS. The LOS reduction seen in our study is clinically meaningful. Notably, other measures of patient outcomes and quality of care metrics did not change significantly, and some trended towards improvement.

Nitric oxide in central amygdala potentiates expression of conditioned withdrawal induced by morphine.

OBJECTIVE: The aim of this study was to evaluate if nitric oxide (NO) in the central amygdala (CeA) is involved in the expression of withdrawal aspects induced by morphine. MATERIALS AND METHODS: Male Wistar rats (weighing 200-250 g) were bilaterally cannulated in the CeA and conditioned to morphine using an unbiased paradigm. Morphine (2.5-10 mg/kg) was subcutaneously injected once a day throughout the conditioning phase of the procedure. This phase also included 3-saline paired sessions. Naloxone (0.1-0.4 mg/kg, intraperitoneally [i.p.]), an antagonist of opioid receptors, was administered i.p. 10 min prior to testing of morphine-induced withdrawal features. The NO precursor, L-arginine (0.3-3 µg/rat) was intra-CeA injected prior to testing of naloxone response. To evaluate the involvement of NO system an inhibitor of NO synthase (NOS), N(G)-nitro-L-arginine methyl ester (L-NAME) (0.3-3 µg/rat), was injected ahead of L-arginine. Control group received saline solely instead of drug. As a complementary study, the activation of NOS was studied by nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d). RESULTS: Morphine induced a significant increase in wet dog shaking and grooming behaviors compared with controls. Injection of naloxone pre-testing of morphine response significantly reversed the response to morphine. However, pre-microinjection of L-arginine intra-CeA recovered the response to morphine. Injection of L-NAME intra-CeA ahead of L-arginine though had no effect behaviorally, but, inhibited the NOS which has been evidenced by NADPH-d. CONCLUSION: The present study shows that NO in the CeA potentiates the expression of conditioned withdrawal induced by morphine paired with naloxone.

Efecto analgésico del Lupinus mutabilis S (chocho) comparado con morfina / Analgesic effect of Lupinus mutabilis S (chocho) compared to morphine

El Lupinus mutabilis Sweet es una planta con alto contenido calórico y marcados efectos farmacológicos, por lo que pertenece al grupo de plantas nutracéuticas. Objetivo: Comparar la acción analgésica del Lupinus mutabilis S, con el de la Morfina, utilizando la técnica estandarizada de CYTED, del Plantar-test. Materiales y métodos: Utilizamos 50 ratones albinos, machos, de la cepa Holtzman, de aproximadamente 25 gramos de peso, obtenidos del bioterio del MINSA-Chorrillos, a los que previamente se les acondicionó en el bioterio de la Facultad de Medicina Humana de la Universidad San Martín de Porres y suministró alimento y agua. Se les distribuyó en cinco grupos, G1: Control negativo; G2: Lupinus mutabilis, 300 mg/kg; G3: Lupinus mutabilis, 300 mg/kg + Naloxona, 5 mg/kg; G4: Morfina, 10 mg/kg; y, G5: Morfina, 10 mg/kg + Naloxona, 5 mg/kg. Se determinó el umbral doloroso basal de cada uno de los animales en los diferentes grupos utilizando el test del Hot Plate, el mismo que se repitió a los 30, 60 y 90 ,imutos posteriores a la administración, vía intraperitoneal, de las sustancias correspondientes a cada grupo. Los resultados obtenidos fueron analizados estadisticamente con el programa Graph Pad Prism y Excel XP. Resultados: Apreciamos un efecto analgésico del Lupinus similar al de la Morfina, el mismo que fue bloqueado por Naloxona tanto en el grupo tratado con Morfina como en el tratado con Lupinus mutabilis, a la 1/2 hora. Conclusiones: El Lupinus mutabilis S, mostró un buen efecto analgésico, que al igual que la Morfina fue bloqueado por Naloxona.

Lupinus mutabilis Sweet is a plant with high calorie content and many pharmacological effects; therefore, we consider it as a nutraceutic plant. Objective: The present investigation was made with the purpose of comparing the analgesic properties of Lupinus mutabilis S with Morphine, using the standardized technique of CYTED from Plantar Test. Materials and Method: We used fifty albino mice; male of Holtzman bred weighing 25 grams approximately and got from biotherius at MINSA, Chorrillos, to whom previous conditioning in the biotherius from Facultad de Medicina Humana at Universidad de San Martin de Porres and supply of food and water, distributed in the following five groups, G1: Negative control groups, G2: Lupinus mutabilis 300 mg/kg; G3: Lupinus mutabilis, 300 mg/kg+Naloxoma, 5 mg/kg; G4: Morphine, 10 mg/kg and G5: Morphine. 10 mg/kg+Naloxona, 5 mg/kg. It was determined the basal painful threshold to each one of the animals in different groups, using the test of the Hot Plate, the same thing was repeated at 30, 60 and 90 minutus after administration by intraperitoneal via of substances according to each group. The results were analyzed statistically with the program GraphPad Prism and Excel XP. Results: We appreciate an analgesic effect of Lupinus mutabilis Sweet similar to morphine, the same that was blocked by Naloxone in both group treated with Morphine and Lupinus mutabilis at the first 30 minutes. Conclusions: Lupinus mutabilis Sweet showed a good pharmacological action, which like to Morphine that was blockaded by Naloxone.