Abstract Morus nigra has been used to relieve pain in Brazilian folk medicine. This study was conducted to establish the antinociceptive properties of dichloromethane extract from leaves of M. nigra. The formalin, hot plate, and tail immersion tests as well as acetic acid-induced writhing were used to investigate the antinociceptive activity in mice. The extract at test doses of 100 and 300 mg/kg, p.o. clearly demonstrated antinociceptive activity in all tests. The extract administered at 300 mg/kg, p.o. had a stronger antinociceptive effect than indomethacin (5 mg/kg, p.o.) and morphine (10 mg/kg, p.o.), which supports previous claims for its traditional use. less...

Pain in patients with impaired renal function may be a significant problem requiring treatment with opioids. However, pharmacokinetic and metabolic changes associated with an impaired renal function may raise some concerns about side effects and overdosing associated with opioid agents in this patient's population. In order to give recommendations on this issue, we review the available evidences on the pharmacokinetics and side effects of most common opioids used to treat pain. The results of this review show that the half-life of the parent opioid compounds and of their metabolites is increased in the presence of renal dysfunction, for which careful monitoring of the patient, dose reduction and a longer time interval between doses are recommended. Among opioids, morphine and codeine used with very caution and possibly avoided in renal failure/dialysis patients; tramadol, hydromorphone and oxycodone can be used with caution and close patient's monitoring, whereas transdermal buprenorphine, methadone and fentanyl/sufentanil appear to be safe to use in patients with renal failure. less...

Human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) have been shown to compartmentalize within various tissues, including the brain. However, the evolution of viral quasispecies in the setting of drug abuse has not been characterized. The goal of this study was to examine viral evolution in the cerebral compartment of morphine-dependent and control macaques to determine its role in rapid disease progression. To address this issue, we analyzed the envelope (env) gene from proviral DNA in our SIV/SHIV macaque model of morphine dependence and AIDS. Analyses of proviral DNA revealed a direct correlation between total genetic changes and survival time. However, the rate of evolution during disease progression was higher in morphine-dependent and rapid-progressor macaques than was the rate of evolution in the control animals. This study provides additional insight into SIV envelope variation in the CNS of morphine-dependent macaques and genotypes that may have evolved in the brain and contributed to disease progression. less...

Background: Harvesting of iliac crest graft for spinal fusions is associated with a number of patients reporting residual or chronic pain at the harvest site. Various interventions, including morphine infiltration, have been proposed to minimize the associated pain. Methods: We performed a prospective, double-blind, randomized, placebo-controlled study comparing intraoperative infiltration of 5 mg morphine (treatment) versus saline (placebo) into the iliac crest harvest site for patients undergoing elective spinal surgery. Patients with myelopathy, excessive perioperative opioid use (60 mg equivalent morphine/d or more), or multilevel (>3 levels) spinal surgery were excluded. Postoperative administration of morphine (recovery room and patient-controlled analgesia) was standardized. Numerical pain scores specific for the iliac crest site were determined in the immediate postoperative period and at 3, 6, and 12 months. Results: Of the 54 patients randomized, 47 (87%) were available for review with a minimum of 1-year follow-up. The groups were similar in baseline age, gender, and comorbidities. There was no significant difference between groups in total use of postoperative morphine during the first 24 hours (P = 0.48). Repeated measures analysis of variance demonstrated no interacting effect of group over time for hip pain at rest (P = 0.94), hip pain while moving (P = 0.90), spine pain at rest (P = 0.99), or spine pain while moving (P = 0.83). The proportion of patients reporting iliac crest pain at 1-year follow-up was the same between groups (P = 0.95). Conclusions: This study has demonstrated that there are no additional benefits for the use of intraoperative infiltration of morphine into the iliac crest harvest site during spinal fusions. less...

Patients prescribed morphine for the management of chronic pain, and chronic heroin abusers, often present with complications such as increased susceptibility to opportunistic infections and inadequate healing of wounds. We investigated the effect of morphine on wound-healing events in the presence of an infection in an in vivo murine model that mimics the clinical manifestations seen in opioid user and abuser populations. We show for the first time that in the presence of an inflammatory inducer, lipopolysaccharide, chronic morphine treatment results in a marked decrease in wound closure, compromised wound integrity, and increased bacterial sepsis. Morphine treatment resulted in a significant delay and reduction in both neutrophil and macrophage recruitment to the wound site. The delay and reduction in neutrophil reduction was attributed to altered early expression of keratinocyte derived cytokine and was independent of macrophage inflammatory protein 2 expression, whereas suppression of macrophage infiltration was attributed to suppressed levels of the potent macrophage chemoattractant monocyte chemotactic protein-1. When the effects of chronic morphine on later wound healing events were investigated, a significant suppression in angiogenesis and myofibroblast recruitment were observed in animals that received chronic morphine administration. Taken together, our findings indicate that morphine treatment results in a delay in the recruitment of cellular events following wounding, resulting in a lack of bacterial clearance and delayed wound closure. less...

In the striatum, signaling through G protein-coupled dopamine receptors mediates motor and reward behavior, and underlies the effects of addictive drugs. The extent of receptor responses is determined by RGS9-2/Gbeta5 complexes, a striatally enriched regulator that limits the lifetime of activated G proteins. Recent studies suggest that the function of RGS9-2/Gbeta5 is controlled by the association with an additional subunit, R7BP, making elucidation of its contribution to striatal signaling essential for understanding molecular mechanisms of behaviors mediated by the striatum. In this study, we report that elimination of R7BP in mice results in motor coordination deficits and greater locomotor response to morphine administration, consistent with the essential role of R7BP in maintaining RGS9-2 expression in the striatum However, in contrast to previously reported observations with RGS9-2 knockouts, mice lacking R7BP do not show higher sensitivity to locomotor-stimulating effects of cocaine. Using a striatum-specific knockdown approach, we show that the sensitivity of motor stimulation to cocaine is instead dependent on RGS7, whose complex formation with R7BP is dictated by RGS9-2 expression. These results indicate that dopamine signaling in the striatum is controlled by concerted interplay between two RGS proteins, RGS7 and RGS9-2, which are balanced by a common subunit, R7BP.Neuropsychopharmacology advance online publication, 30 December 2009; doi:10.1038/npp.2009.212. less...

Objective-To compare the effects of intra-articular (IA) versus IV administration of morphine on local and systemic inflammatory responses in horses with experimentally induced acute synovitis. Animals-8 horses. Procedures-Each horse received the following 2 treatments 4 hours after synovitis was induced: IA administration of morphine (0.05 mg/kg) with IV administration of 1 mL of saline (0.9% NaCl) solution/100 kg, and IA administration of 1 mL of saline solution/100 kg with IV administration of morphine (0.05 mg/kg). Treatments were administered in randomized order with a washout period of 3 weeks between treatments. Before each treatment, aseptic synovitis was induced by injection of lipopolysaccharide into a radiocarpal joint. For the second treatment, the contralateral radiocarpal joint was selected. Joint swelling and skin temperature over the treated joints were recorded. Clinical examinations were performed, and blood WBC count, serum amyloid A (SAA) concentration, serum cortisol concentration, synovial fluid WBC count, synovial fluid total protein (TP) concentration, and synovial fluid SAA concentration were measured before and repeatedly during each of the two 168-hour study periods. Data were analyzed by use of ANOVA with repeated measures. Results-IA administration of morphine resulted in significantly less joint swelling and lower synovial fluid TP and serum and synovial fluid SAA concentrations, and blood WBC count than did IV administration of morphine. Conclusions and Clinical Relevance-IA administration of morphine exerted anti-inflammatory properties in horses with experimentally induced acute synovitis, supporting its use as a part of a balanced analgesic protocol. less...

The neurobiological substrate for morphine self-administration in animals is believed to involve the dopamine system of the nucleus accumbens. Our previous study has shown that acupuncture at the acupoint Shenmen (HT7) reduced dopamine release in the nucleus accumbens and behavioral hyperactivity induced by systemic administration of morphine. Here we investigated the effect of acupuncture on morphine self-administration and potential roles of GABA receptors in the mechanisms behind acupuncture. Male Sprague-Dawley rats were trained to self-administer morphine (0.1mg/kg per infusion) during daily 1-h session under fixed ratio 1 schedule. Following the stable responding on morphine self-administration, acupuncture was applied to HT7 points bilaterally (1min) prior to the testing session. Another groups of rats were given the GABA(B) receptor antagonist SCH 50911 (3.0mg/kg, i.p.), the GABA(A) receptor antagonist bicuculline (1.0mg/kg, i.p.) or saline 30min prior to the acupuncture treatment. We have found that acupuncture at the acupoint HT7, but not at the control point Yangxi (LI5), significantly decreased morphine self-administration. Moreover, either SCH 50911 or bicuculline blocked the inhibitory effects of acupuncture on morphine self-administration. Taken together, the current results suggest that acupuncture at specific HT7 points regulates the reinforcing effects of morphine via regulation of GABA receptors. less...

Our laboratory studies the effects of in utero opioid exposure on the neonate. In this work we test the effects of chronic in utero exposure to buprenorphine on the neonate. Buprenorphine is a promising candidate for treatment of opioid addiction during pregnancy and it has been suggested to decrease the neonatal abstinence syndrome in human infants. In our guinea pig model, we focused not only on the respiratory effects of in utero exposure on the neonate, but also studied withdrawal signs in the neonate, a major concern of all opioid treatment during pregnancy. Pregnant guinea pigs were treated with daily subcutaneous injections of 0.1mg/kg buprenorphine during the second half of gestation. We measured weight, locomotor activity and respiratory function in pups of ages 3 to 14days. Respiratory response was recorded using a two-chamber plethysmograph, while pups were breathing either room air or 5% CO(2). Our results show that chronic in utero exposure to buprenorphine induces respiratory effects up to day 14 after birth, while earlier studies have shown that effects of either in utero methadone or morphine only persist in the first week after birth in the guinea pig model. These data provide important information for clinical trials of buprenorphine treatment suggesting that duration and severity of respiratory effects of in utero buprenorphine exposure should be monitored. less...

Desensitization of the micro-opioid receptor (MOR) has been implicated as an important regulatory process in the development of tolerance to opiates. Monitoring the release of intracellular Ca(2+) ([Ca(2+)](i)), we reported that [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO)-induced receptor desensitization requires receptor phosphorylation and recruitment of beta-arrestins (betaArrs), while morphine-induced receptor desensitization does not. In current studies, we established that morphine-induced MOR desensitization is protein kinase C (PKC)-dependent. By using RNA interference techniques and subtype specific inhibitors, PKCepsilon was shown to be the PKC subtype activated by morphine and the subtype responsible for morphine-induced desensitization. In contrast, DAMGO did not increase PKCepsilon activity and DAMGO-induced MOR desensitization was not affected by modulating PKCepsilon activity. Among the various proteins within the receptor signaling complex, Galphai2 was phosphorylated by morphine-activated PKCepsilon. Moreover, mutating three putative PKC phosphorylation sites, Ser(44), Ser(144) and Ser(302) on Galphai2 to Ala attenuated morphine-induced, but not DAMGO-induced desensitization. In addition, pretreatment with morphine desensitized cannabinoid receptor CB1 agonist WIN 55212-2-induced [Ca(2+)](i) release, and this desensitization could be reversed by pretreating the cells with PKCepsilon inhibitor or overexpressing Galphai2 with the putative PKC phosphorylation sites mutated. Thus, depending on the agonist, activation of MOR could lead to heterologous desensitization and probable crosstalk between MOR and other Galphai-coupled receptors, such as the CB1. less...