Browsing by Subject "Opioid"

Now showing 1 - 9 of 9
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    Association of opioid requirement and cancer pain with survival in advanced non-small cell lung cancer
    (2017-05) Zylla, Dylan
    Background: Pain is associated with shorter survival in non-small cell lung cancer (NSCLC). Lung cancer cells express opioid receptors. Opioids promote angiogenesis, tumor growth and metastases, and shorten survival in animal models. Methods: To examine if long-term opioid requirement, independently of chronic pain, is associated with survival, we studied 209 patients treated with chemotherapy for stage IIIB/IV NSCLC. Pain was stratified by proportion of time patients reported specific levels of pain. Opioids were converted to oral morphine equivalents (OME) for comparison. The effects of pain, opioid requirement, and known prognostic variables on survival were analyzed in univariable and multivariable models. Results: Both severity of pain and greater opioid requirement in first 90 days after starting chemotherapy were strongly predictive of shorter survival on univariable analysis. Patients with no/mild chronic pain and requiring <5 mg/day OME during first 90 days had nearly 12 months longer median survival compared to patients requiring ≥5 mg/day OME and/or experiencing more pain. Differences in survival remained remarkably similar when chronic pain and opioid requirement were assessed over the entire clinical course (until death or last follow-up). In multivariable models, both opioid requirement and chronic pain remained independent predictors of survival, after adjustment for age, stage and performance status. Conclusions: Severity of chronic cancer-related pain or greater opioid requirement are associated with shorter survival in advanced NSCLC, independently of known prognostic factors. While pain adversely influences prognosis, controlling it with opioids does not improve survival. Prospective studies should determine if achieving pain control using opioid-sparing approaches improves outcomes.
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    Differential regulation of opioid receptors during inflammation
    (2009-07) Satterfield, Catherine Suzanne
    Properties of the opium poppy have been exploited for centuries for the alleviation of pain and to induce euphoria. Classically thought to produce its effects solely in the central nervous system, peripheral opioid analgesic systems are now widely accepted. The activation of these systems leads to a reduction in primary afferent fiber excitability leading to the inhibition of sensory transduction. Opioid receptors function is modulated by a variety of mechanisms. An example of this is enhanced peripheral opioid receptor function following inflammation. The present study examined peripheral opioid receptor regulation in early and late stages of CFA inflammation. Additionally, a new model of UVB of inflammation was characterized. Peripheral MOR receptors are differentially regulated in late and early CFA inflammation. Peripheral MOR is not responsible for attenuated responses of nociceptors to mechanical stimuli 18 hours after CFA inflammation. DAMGO reduced mechanical responsiveness of nociceptors at 72 hours after CFA inflammation in a concentration and antagonist reversible manner indicating that MOR efficacy is enhanced during later stages of CFA inflammation. UVB produced severe but localized inflammation that differed from inflammation produced by CFA. This inflammation sensitizes nociceptor units innervating irradiated skin and results in enhanced peripheral opioid receptor efficacy.
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    Dynamic regulation of R7BP (R7 Binding Protein) containing R7 RGS (R7 Regulators of G protein Signaling) protein complexes: role in controlling neuronal dopamine and opioid signaling in the striatum.
    (2010-02) Anderson, Garret R.
    G protein-coupled receptor (GPCR) signaling pathways mediate the transmission of signals from the extracellular environment to the generation of cellular responses, a process that is critically important for neurons and neurotransmitter action. The ability to promptly respond to rapidly changing stimulation requires timely inactivation of G proteins, a process controlled by a family of specialized proteins known as regulators of G protein signaling (RGS). The R7 group of RGS proteins (R7 RGS) has received special attention due to their pivotal roles in the regulation of a range of crucial neuronal processes such as vision, motor control, reward behavior and nociception in mammals. One member of the R7 RGS family, RGS9-2 has been previously implicated as an essential modulator of signaling through neuronal dopamine and opioid G protein coupled receptors. RGS9-2 is specifically expressed in striatal neurons where it forms complexes with R7BP (R7 RGS Binding Protein), which we have found to ultimately affect several critical properties of RGS9-2. First, it is this interaction with R7BP which is necessary for determining the subcellular targeting of RGS9-2 to the plasma membrane and to the specialized neuronal compartment of excitatory synapses, the postsynaptic density. Secondly, R7BP plays a selective role amongst the R7 RGS family in determining the proteolytic stability of RGS9-2. Further characterization of R7 RGS complexes in the striatum revealed that two equally abundant R7 RGS proteins, RGS9-2 and RGS7, are unequally coupled to the R7BP subunit which is present in complex predominantly with RGS9-2 rather than with RGS7. However, upon changes in neuronal activity the subunit composition of these complexes in the striatum undergoes rapid and extensive remodeling. Changes in the neuronal excitability or oxygenation status result in extracellular calcium entry, uncoupling RGS9-2 from R7BP, triggering its selective degradation. Concurrently, released R7BP binds to cytoplasmic RGS7 and recruits it to the plasma membrane and the postsynaptic density. These observations introduce activity dependent remodeling of R7 RGS complexes as a new molecular plasticity mechanism in striatal neurons and suggest a general model for achieving rapid posttranslational subunit rearrangement in multi-subunit complexes. The physiological consequence of this remodeling process appears to play a role in determining the signaling sensitivity to dopamine stimulation. Considering that upon the genetic elimination of RGS9, all available R7BP is funneled towards complex formation with RGS7, not only are RGS9 controlled GPCR signaling pathways affected, but those controlled by RGS7 as well. RGS9 knockout mice have an increased sensitivity to dopamine and opioid receptor stimulation and consequently display altered motor and reward behavior. The question arises as to the role of modulation of RGS7 function in controlling these behaviors. Since the function of RGS9-2 is controlled by its association with R7BP, we would predict that the elimination of R7BP would lead to similar alterations in striatal physiology for RGS9 controlled pathways. While at the same time, RGS7 would be largely unaffected by the elimination of R7BP, thus RGS7 controlled pathways would predictably remain unaltered. Using this rationale, 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 RGS9 in controlling these behaviors and the critical role played by 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 exhibit higher sensitivity to locomotor-stimulating effects of cocaine, suggesting a role for RGS7 in controlling dopamine sensitivity. Using a striatum-specific knockdown approach, we demonstrate that the sensitivity of motor stimulation to cocaine is indeed dependent on RGS7 function. 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.
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    Elucidating the role of opioid receptor heteromers as targets for analgesic drug design
    (2011-10) Yekkirala, Ajay S.
    Opioid receptors are class A members of the G protein coupled-receptor (GPCR) superfamily. There is high amino acid homology (~60%) within the opioid receptor family that constitutes a group of four receptor types: MOP (mu), DOP (delta), KOP (kappa), and NOP (nociceptin, orphanin FQ, ORL1). Opioid receptors are present in the central nervous system and peripherally, including immune cells, and are believed to function as neuromodulators or immunomodulators. Morphine is among the best known clinically employed analgesics that activate opioid receptors. Although the concept of opioid receptor dimers was proposed nearly 30 years ago, classical models of GPCRs, including opioid receptors, were generally based on the assumption that they are organized and function as monomers. However, in view of burgeoning evidence for the existence of heteromeric GPCRs, that includes at least twelve different heteromeric opioid receptors in cultured cells, it seems likely that constitutive oligomerization of GPCRs may be the general rule rather than the exception. Among the many heteromers reported in the opioid receptor family are mu/kappa, kappa/delta and mu/delta. However, the in vivo physiological and behavioral relevance for the proposed heteromers have not yet been rigorously established. The greatest drawback in studying the signaling and trafficking properties of heteromers pertains to the lack of selective ligands targeting opioid heteromers. It is, therefore, necessary to first develop tools that can be used as probes to address the shortcomings. Hence, we evaluated standard opioids agonists and antagonists, novel ligands synthesized in our lab, and clinically used opioid analgesics to establish a ligand selectivity profile that takes into account the existence of heteromers. Utilizing mu-delta agonist/antagonist bivalent ligands we have provided direct evidence for bridging of opioid receptor heteromers using immunofluorescent methods. Moreover, we performed studies to elucidate how the individual protomers constituting a heteromer modulate the trafficking and functional properties of each other. The results have painted an intriguing picture suggesting that the effects are dependent on both protomer composition and the ligands used. Those studies have given us valuable information on the role of opioid heteromers in physiology, and as unique targets in drug discovery.
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    Endogenous modulation of addiction: chronic pain and the NMDA/NOS cascade.
    (2010-07) Wade, Carrie Lynn
    Opioid treatment for chronic pain is controversial due to abuse potential and perceived addiction potential. Because of perceptions of addiction from chronic opioid treatment for pain it is important to clearly understand the biological bases for a number of factors related to opioid therapy in the context of chronic pain, including the effectiveness of opioid treatment under distinct conditions chronic pain and alterations in the effectiveness of opioid treatment under distinct conditions of chronic opioid pharmacotherapy. One way to approach this question is to study the changes that occur with chronic pain and see how those changes parallel those that occur with opioid addiction. Our approach to address the questions raised above is to apply a combination of rodent models of pain and opioid self-administration. In the first phase of this study we examine changes in oral fentanyl self-administration under distinct conditions of chronic pain including inflammatory pain, neuropathic pain and an idiopathic pain model of sickle cell anemia. The second set of studies examines the potential for an endogenous modulator of the NMDA/NOS cascade to interact with adverse opioid events such as tolerance and addiction. We observed that mice with inflammatory pain, neuropathic pain and sickle cell anemia had differential fentanyl self-administration profiles following induction of mechanical hyperalgesia. In the second set of studies we observed that agmatine reduced opioid-induced tolerance and abolished self-administration behaviors. We also found that endogenous agmatine may have a neuroprotective effect on these opioid effects.
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    A heroin/morphine vaccine: mechanism of action and extending its use to other abused opioids
    (2013-07) Raleigh, Michael Dennis
    Heroin is more widely used than any other illicit opioid and mortality rates among heroin users are an average of 13 times higher than the general population. Intravenous heroin use is associated with crime, social disruption, and transmission of blood-born pathogens such as human immunodeficiency virus and hepatitis C. Effective pharmacotherapies are available to treat heroin abuse but have been largely unsuccessful because they require frequent dosing, have a high abuse potential, or have low compliance. Vaccines against heroin and its metabolites (e.g. morphine) are being considered as a complementary treatment for heroin abuse because they are long-acting, selective, have no abuse potential, and may benefit those unwilling to take the current pharmacotherapies. Vaccination with morphine-conjugate vaccines can elicit a strong immune response that reduces the behavioral effects of heroin in animals, presumably by morphine-specific antibodies binding opioids in blood and reducing their distribution to brain. This thesis explores the use of M-KLH, a morphine hapten conjugated to keyhole limpet hemocyanin (KLH) using a tetraglycine linker and mixed with either Freund's or alum adjuvant for increasing the immune response. Morphine vaccines present many challenges that make translation to clinical use difficult. Heroin is sequentially metabolized to its active intermediates 6-monoacetylmorphine (6-MAM), morphine, and then to morphine-6-glucuronide (in vivo and ex vivo). Heroin enters brain and is rapidly converted to 6-MAM, which is presumed to mediate most of heroin's early effects. With regard to the mechanism of action of morphine vaccines, it is unclear whether the antibodies they generate must bind heroin, its downstream metabolites, or both to prevent opioid distribution from plasma to brain and reduce heroin's behavioral effects. However, because analytical assays to measure heroin and metabolite concentrations in tissues have used a wide range of conditions and varying degrees of stability have been reported, studying the effect of vaccination on heroin distribution is not straightforward. In addition, heroin and metabolite distribution after i.v. heroin administration, the most common route of abuse by humans, has not been well characterized in non-vaccinated rodents. Finally, blockade of heroin by vaccination may not prevent the abuse of structurally distinct opioids. The overall goal of this thesis was to better understand the mechanism of action of morphine vaccines and to extend their use to other abused opioids. The specific aims were to stabilize heroin in blood and brain tissues for subsequent pharmacokinetic studies, study distribution of heroin and its metabolites in non-vaccinated and vaccinated rats, explore the effects of vaccination on heroin-induced behaviors, and determine if vaccine efficacy is retained when combined with a vaccine targeting oxycodone, another commonly abused opioid. These aims were explored using clinically relevant drug doses. Heroin and metabolite degradation was significantly reduced by 1) the addition of ice-cold sodium fluoride (a general esterase inhibitor) and formate buffer (pH 3.0) in heroin-spiked tissues, 2) rapid removal of red blood cells via centrifugation, and 3) drying opioids after extraction from tissues prior to measuring their levels. Using these conditions heroin and its metabolites were stabilized in tissues for subsequent distribution studies. In non-vaccinated rats 6-MAM was the predominant metabolite in brain as early as one minute after administration of 0.26 mg/kg i.v. heroin, which is consistent with previous studies that suggest that 6-MAM mediates heroin's early behavioral effects. Vaccination with a morphine-conjugate vaccine (M-KLH) led to a reduction of 6-MAM and morphine, but not heroin, distribution to brain after heroin administration, suggesting that morphine vaccines reduce accumulation of 6-MAM in brain. The mechanism by which this occurs is likely through antibody binding of 6-MAM in plasma to prevent its distribution to brain and is consistent with very high plasma 6-MAM concentrations in vaccinated rats after i.v. heroin or 6-MAM administration. Vaccination with M-KLH led to a reduction of heroin-induced anti-nociception and locomotor activity and remained effective for up to 16 days after repeated dosing suggesting that heroin vaccines may have long-lasting efficacy. These results are consistent with findings from the distribution studies and support the hypothesis that morphine vaccines function by retaining 6-MAM in plasma and prevent its accumulation in brain. To determine whether opioid vaccines could be combined without reducing individual vaccine efficacy and prevent heroin addicts from abusing structurally distinct opioids, rats were vaccinated with M-KLH, an oxycodone-conjugate vaccine (Oxy-KLH), or the bivalent vaccine (both M-KLH and Oxy-KLH). Total morphine- and oxycodone-specific antibody titers were significantly increased in rats that received the bivalent vaccine compared to rats that received individual vaccines. Concurrent i.v. administration of 6-MAM and oxycodone in M-KLH vaccinated rats led to increased 6-MAM retention in plasma and reduced 6-MAM distribution in brain. A similar effect on oxycodone distribution was seen in Oxy-KLH vaccinated rats. There was a trend towards greater efficacy in altering both 6-MAM and oxycodone distribution in the bivalent group compared to individual vaccine groups. These data suggest that combining opioid vaccines will retain, and possibly enhance, individual vaccine efficacy and might be a viable option to prevent addicts from abusing structurally distinct opioids. These findings contribute to the understanding of how morphine vaccines elicit their effects on heroin-induced behaviors and suggest that morphine vaccines, alone or in combination with other pharmacotherapies, may benefit those seeking treatment for heroin addiction.
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    MMG22: A Novel Bivalent Ligand for the Treatment of Neuropathic Pain
    (2020-10) Speltz Paiz, Rebecca
    Functional interactions between the mu opioid receptor (MOR) and the metabotropic glutamate receptor 5 (mGluR5) in pain and analgesia have been well established. MMG22 is a bivalent ligand containing MOR agonist (oxymorphamine) and mGluR5 antagonist (MPEP) pharmacophores tethered by a 22-atom linker. MMG22 has been shown to produce potent analgesia in several models of chronic inflammatory and neuropathic pain. This study assessed the efficacy of systemic administration of MMG22 at reducing pain behavior in the spared nerve injury (SNI) model of neuropathic pain in mice, as well as its side effect profile and abuse potential. MMG22 reduced mechanical hyperalgesia and spontaneous ongoing pain after SNI, with greater potency early (10 days) as compared to late (30 days) after injury. Systemic administration of MMG22 did not induce place preference in naïve animals, suggesting absence of abuse liability when compared to traditional opioids. MMG22 also lacked the central locomotor, respiratory, and anxiolytic side effects of its monomeric pharmacophores. Evaluation of mRNA expression showed the transcripts for both receptors were co-localized in cells in the dorsal horn of the lumbar spinal cord and dorsal root ganglia. Teased nerve fiber recordings from the sural nerve of SNI mice show that MMG22 reduces the firing rate of C and Aδ fiber nociceptors evoked by suprathreshold stimuli. Thus, MMG22 reduces hyperalgesia after injury in the SNI model of neuropathic pain by decreasing nociceptor activity without the typical centrally mediated side effects associated with traditional opioids.
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    Mu Opioid Receptor Modulation of Social Behavior
    (2022-05) Toddes, Carlee
    Social interaction is a fundamental behavior necessary for the survival of every animal species on earth. These interactions encompass a complex range of behaviors that require coordinated activity of multiple neural circuits for successful expression. While these behaviors have been the focus of intense neuroscientific studies for the last several decades, there remains a dearth of knowledge regarding the specific cells and receptor subsystems that lead to their expression or disruption. This dissertation focuses specifically on uncovering the role of the endogenous opioid system, namely mu opioid receptors, on affiliative social interaction in mice. Since affiliative social interaction encompasses a broad range of social behaviors dependent upon a series of interconnected neural circuits, the first series of experiments were designed to elucidate which swath of behaviors the mu opioid system specifically regulates and pinpoint a neural hub upon which they act. Following the identification of reciprocal interactions as the main behavior modulated by mu opioid receptor expression and the identification of the nucleus accumbens as a key site of cellular reorganization, the second series of experiments were designed to identify specific cellular elements within the nucleus accumbens that modulate reciprocal social interactions.
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    Neuroligin-3 Modulates Opioid-Evoked Changes in Behavior and Brain Function
    (2022-05) Brandner, Dieter
    Chronic opioid exposure causes structural and functional changes in brain circuits, which may contribute to opioid use disorders. Synaptic cell-adhesion molecules are prime candidates for mediating this opioid-evoked plasticity. Neuroligin-3 is a postsynaptic adhesion protein that shapes synaptic function at multiple sites in the mesolimbic dopamine system. We therefore studied how genetic knockout of neuroligin-3 alters responses to chronic morphine in male mice. Constitutive neuroligin-3 knockout caused a persistent reduction in psychomotor sensitization after chronic morphine exposure, as well as a change in the topography of locomotor stimulation produced by morphine. This latter change was recapitulated by conditional genetic deletion of neuroligin-3 from cells expressing the Drd1 dopamine receptor, whereas the reduction in psychomotor sensitization was recapitulated by conditional genetic deletion from dopamine neurons. In the absence of neuroligin-3 expression, dopamine neurons within the ventral tegmental area showed diminished activation following chronic morphine exposure, as measured by in vivo calcium imaging with fiber photometry. This altered pattern of dopamine neuron activity may be driven by aberrant forms of opioid-evoked synaptic plasticity in the absence of neuroligin-3: dopamine neurons lacking neuroligin-3 showed weaker synaptic inhibition at baseline, which was subsequently strengthened after chronic morphine. In total, our study highlights neurobiological adaptations in dopamine neurons of the ventral tegmental area that correspond with increased behavioral sensitivity to opioids, and further suggests that neuroligin-3 expression by dopamine neurons provides a molecular substrate for opioid-evoked adaptations in brain function and behavior.