The Contribution of the Descending Pain Modulatory Pathway in Opioid Tolerance

Opioids remain among the most effective pain-relieving therapeutics. However, their long-term use is limited due to the development of tolerance and potential for addiction. For many years, researchers have explored the underlying mechanisms that lead to this decreased effectiveness of opioids after repeated use, and numerous theories have been proposed to explain these changes. The most widely studied theories involve alterations in receptor trafficking and intracellular signaling. Other possible mechanisms include the recruitment of new structural neuronal and microglia networks. While many of these theories have been developed using molecular and cellular techniques, more recent behavioral data also supports these findings. In this review, we focus on the mechanisms that underlie tolerance within the descending pain modulatory pathway, including alterations in intracellular signaling, neural-glial interactions, and neurotransmission following opioid exposure. Developing a better understanding of the relationship between these various mechanisms, within different parts of this pathway, is vital for the identification of more efficacious, novel therapeutics to treat chronic pain

The Contribution of the Descending Pain Modulatory Pathway in Opioid Tolerance

Opioids remain among the most effective pain-relieving therapeutics. However, their long-term use is limited due to the development of tolerance and potential for addiction. For many years, researchers have explored the underlying mechanisms that lead to this decreased effectiveness of opioids after repeated use, and numerous theories have been proposed to explain these changes. The most widely studied theories involve alterations in receptor trafficking and intracellular signaling. Other possible mechanisms include the recruitment of new structural neuronal and microglia networks. While many of these theories have been developed using molecular and cellular techniques, more recent behavioral data also supports these findings. In this review, we focus on the mechanisms that underlie tolerance within the descending pain modulatory pathway, including alterations in intracellular signaling, neural-glial interactions, and neurotransmission following opioid exposure. Developing a better understanding of the relationship between these various mechanisms, within different parts of this pathway, is vital for the identification of more efficacious, novel therapeutics to treat chronic pain

Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.

Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long-term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids' lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non-opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research

Addressing opioid tolerance and opioid-induced hypersensitivity: Recent developments and future therapeutic strategies.

Opioids are a commonly prescribed and efficacious medication for the treatment of chronic pain but major side effects such as addiction, respiratory depression, analgesic tolerance, and paradoxical pain hypersensitivity make them inadequate and unsafe for patients requiring long-term pain management. This review summarizes recent advances in our understanding of the outcomes of chronic opioid administration to lay the foundation for the development of novel pharmacological strategies that attenuate opioid tolerance and hypersensitivity; the two main physiological mechanisms underlying the inadequacies of current therapeutic strategies. We also explore mechanistic similarities between the development of neuropathic pain states, opioid tolerance, and hypersensitivity which may explain opioids' lack of efficacy in certain patients. The findings challenge the current direction of analgesic research in developing non-opioid alternatives and we suggest that improving opioids, rather than replacing them, will be a fruitful avenue for future research

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

For centuries, opiate analgesics have had a considerable presence in the treatment of moderate to severe pain. While effective in providing analgesia, opiates are notorious in exerting many undesirable adverse reactions. The receptor targets and the intracellular effectors of opioids have largely been identified. Furthermore, much of the mechanisms underlying the development of tolerance, dependence, and withdrawal have been delineated. Thus, there is a focus on developing novel compounds or strategies in mitigating or avoiding the development of tolerance, dependence, and withdrawal. This review focuses on the adenylyl cyclase and cyclic adenosine 3,5-monophosphate (cAMP)/protein kinase A (AC/cAMP/PKA) system as the central player in mediating the acute and chronic effects of opioids. This chapter also reviews the neuronal adaptive changes in the locus coeruleus, amygdala, periaqueductal gray, and ventral tegmental area induced by acute and chronic actions of opioid because these neuronal adaptive changes in these regions may underlie the behavioral changes observed in opiate users and abusers

The Role of the Recently Deorphanized G-Protein Coupled Receptor, GPR171, in Morphine Tolerance and Withdrawal

Opioid analgesics, such as morphine, represent the gold standard pain killer and the most frequently used drugs for the treatment of moderate to severe pain. Despite being a potent analgesic, morphine has unwanted and dangerous side effects with repeated use, such as tolerance and withdrawal. Tolerance is a state when a person no longer responds to a drug and a higher dose is required to achieve the same initial pain relief. Withdrawal is a set of undesirable psychological and physiological symptoms that occur after someone stops taking a drug or reduces the dose. Morphine tolerance and withdrawal play a vital role in the development of opioid addiction. One of the crucial goals to reduce opioid addiction is to develop pain therapeutics for chronic pain with high efficacy and reduced side effects. Despite centuries of extensive research, the existing treatments for chronic pain have met with limited success and developing better and alternative therapies are urgently needed. A novel G-protein coupled receptor, GPR171, is found to be highly expressed throughout the pain modulating regions of the brain. Our previous study found that activating this receptor with an agonist, enhances morphine’s pain relieving property in combination therapy during acute treatment in mice. In this study, we investigated the effects of activating this receptor during long-term morphine treatment to evaluate tolerance and withdrawal. Our results demonstrate that, activating this receptor reduces morphine induced tolerance in female mice (but not males) on a thermal pain test and it does not have any additional adverse effects on morphine tolerance and withdrawal syndrome. These results suggest the potentiality of GPR171 as a novel pain therapeutics in combination with morphine with enhanced efficacy and reduced tolerance and dependence for the treatment of chronic pain, especially for females

Studies on the Role of G Protein Alpha Subunits in Opioid Signaling and Behavior.

Opioids (e.g. morphine) are powerful analgesics that are used clinically to treat a variety of pain conditions. However, chronic use of opioids is associated with the development of adaptations such as tolerance and dependence, which limit their utility as long-term pain therapeutics. Opioids produce analgesia by activating mu opioid receptors that are located on both central and peripheral nerve terminals. The mu opioid receptor is a G protein-coupled receptor that activates inhibitory heterotrimeric G proteins composed of a G(alpha)i/o subunit and a (beta)(gamma) heterodimer via nucleotide exchange. Once activated, these G protein subunits modulate the activity of a number of downstream effectors, including adenylate cyclase and various ion channels. G protein signaling is terminated by the intrinsic GTP hydrolysis of the G(alpha) subunit, although this process is accelerated in vivo by regulator of G protein signaling (RGS) proteins. The goal of the work described in this thesis was to evaluate the role of G(alpha)o protein and its regulation by RGS proteins in opioid-mediated behaviors. G(alpha)o is the most abundant G(alpha)i/o subtype in the brain and has been shown to couple preferentially to the mu opioid receptor. In addition, individual RGS subtypes have been demonstrated to play important roles in opioid-mediated behaviors, but it is not known if endogenous RGS proteins exert their effects through direct binding to G(alpha)i/o subunits or by some other mechanism. To study this, opioid-mediated signaling and behaviors were measured in two different transgenic mouse models, one with a one with targeted knockout of G(alpha)o protein (G(alpha)o knockout mice) and the other with targeted knock-in of an RGS-insensitive mutant G(alpha)o protein (G(alpha)o RGSi mice). Together, these studies demonstrated that mu opioid receptor coupling to G(alpha)o is important for the production of opioid antinociception, and that RGS proteins regulate this response by directly interacting with G(alpha)o subunits. This work also showed that G(alpha)o is protective against morphine tolerance and dependence. Overall, these findings suggest that the RGS:G(alpha)o interface could be a potential target for the development of improved analgesics that are devoid of unwanted adaptations.PHDPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/98076/1/jathom_1.pd

SPINAL KAPPA OPIOID RECEPTOR ACTIVITY INHIBITS ADENYLYL CYCLASE-1 DEPENDENT MECHANISMS OF CHRONIC POSTOPERATIVE PAIN

Chronic postoperative pain impacts millions of individuals worldwide that undergo a variety of surgical procedures. Opioids remain the mainstay analgesics of acute and perioperative pain; however, prolonged opioid therapy may lead to life-threating adverse effects, tolerance, dependence, and addiction. Therefore, unraveling the cellular mechanisms that drive persistent pain states and opposing endogenous analgesia provided by opioid receptor signaling, may lead to novel analgesics. Evidence suggests that tissue injury leads to increased sensitization of the spinal cord nociceptive neurons which increases susceptibility to chronic pain via an N-methyl-D-aspartate (NMDA) receptor activation of calcium-sensitive adenylyl cyclase isoform 1 (AC1). This phenomenon, named latent pain sensitization (LS), is mediated by a compensatory response of endogenous inhibitory systems. In this dissertation, we test the hypothesis that surgical insult promotes prolonged activation of kappa opioid receptors (KOR) which mask LS via attenuation of pro-nociceptive AC1 signaling pathways in both male and female animals. We employed a murine model of chronic postoperative pain that promotes LS in the spinal cord and closely resembles the phenotypic features of postoperative pain in human subjects. When behavioral signs of hyperalgesia resolved, we targeted spinal opioid receptor systems and pronociceptive modulators with intrathecal delivery of selective pharmacological antagonists and assessed behavioral signs of hyperalgesia and spinal nociceptive sensitization. We propose that LS is kept in remission by a long-lasting compensatory response of tonic endogenous KOR signaling that hinders a pronociceptive LS pathway that includes not only AC1 but also two downstream targets: protein kinase A (PKA) and exchange protein activated by cAMP (Epac1/2) - in a sex-dependent manner. Our results propose new therapeutic targets for the management of persistent postoperative pain and underscore the importance of tailoring sex-specific pain management strategies

New insights into enhancing morphine analgesia : from glia to pharmacokinetics

Opioid analgesics are effective in relieving acute and chronic pain. However, adverse effects and the development of opioid dependence and tolerance may restrict the use of opioids and result in inadequate pain relief. The effects of four structurally and functionally different drugs already on the market, ibudilast, atipamezole, spironolactone, and ketamine, were studied in coadministration with morphine, the prototypical mu-opioid receptor agonist. Experiments were conducted using thermal and mechanical tests of nociception in male Sprague-Dawley rats. Morphine tolerance was produced during four days by subcutaneous or intrathecal delivery of morphine. Drug and metabolite concentrations were measured using high-pressure liquid chromatography-tandem mass spectrometry. The objective of the thesis study was to search for potential drugs to augment morphine antinociception and prevent opioid tolerance. Ibudilast, a phosphodiesterase and macrophage inhibitory factor inhibitor, had transient sedative effects, but it restored the antinociceptive effect of morphine in morphine-tolerant rats after single and repeated administration. It did not prevent the development of opioid tolerance. Atipamezole, an alpha-2-adrenoceptor antagonist used for the reversal of sedation in animals during anesthesia, was effective in augmenting intrathecal morphine antinociception in both opioid-naïve and opioid-tolerant animals. These effects were observed at doses lower than those required for the antagonism of alpha-2-adrenoceptors. In subcutaneous administration, low doses of atipamezole did not influence morphine antinociception. The mineralocorticoid receptor antagonist spironolactone dose-dependently enhanced morphine antinociception. This effect was mediated via the increased access of morphine to the central nervous system by the inhibition of the efflux protein P-glycoprotein. Spironolactone did not inhibit the metabolism of morphine to the pronociceptive metabolite morphine-3-glucuronide, and it did not prevent the development of opioid tolerance. The effects of ketamine in augmenting opioid analgesia in tolerance are thought to result from a beneficial pharmacodynamic interaction. When acute ketamine was administered to rats under chronic morphine treatment, the brain concentrations of morphine, ketamine and norketamine were increased compared with the situation where either morphine treatment or acute ketamine were administered alone. The results indicate a potentially beneficial pharmacokinetic interaction between the two drugs. The results of the thesis study demonstrate that ibudilast and atipamezole modulate nociception at systemic and spinal levels in preclinical models of pain, and they may prove advantageous as an adjuvant to opioid therapy. Spironolactone had a pharmacokinetic interaction with morphine, leading to increased morphine concentrations in the central nervous system. Ketamine, a drug used for the treatment of opioid tolerance in cancer patients, may undergo previously unrecognized beneficial pharmacokinetic interactions with morphine.Opioidit, morfiinin kaltaiset kipulääkkeet, ovat tehokkaimpia lääkkeitä etenkin akuutin kivun hoidossa. Haittavaikutukset ja opioideille muodostuva toleranssi eli sietokyvyn lisääntyminen saattavat kuitenkin rajoittaa opioidien käyttöä ja johtaa epätyydyttävään kivun lievitykseen pitkittyneessä kivussa. Tässä tutkimuksessa tarkasteltiin neljää sekä rakenteellisesti että toiminnallisesti erilaista lääkettä, ibudilastia, atipametsolia, spironolaktonia ja ketamiinia, kokeellisissa opioidihoidon rottamalleissa. Tutkimuksessa käytettiin ihmisillä käytettävien kiputestien kaltaisia kuuman ja mekaanisen kivun väistötestejä sekä sedaatiota ja koordinaatiota mittaavia testejä. Opioidihoidon eri vaiheita mallinnettiin aina akuutista kerta-annosta nelipäiväiseen opioditoleranssimalliin. Opioideja ja tutkimuslääkkeitä annettiin joko nahanalaisesti tai suoraan aivo-selkäydinnesteeseen tutkimusmallista ja -lääkkeestä riippuen. Lääkkeiden ja niiden hajoamistuotteiden pitoisuuksia mitattiin kromatografialla. Tutkimuksen tarkoituksena oli etsiä uusia lääkehoitomahdollisuuksia opioidihoidon tehostamiseksi ja etenkin opioidien vasteen palauttamiseksi. Astmalääke ibudilastia on tutkittu usean neurologisen sairauden hoitoon mahdollisen keskushermoston gliasolujen patologisen aktivaation estäjänä. Sillä oli rottamallissa lievä sedatiivinen vaikutus, mutta se palautti tehokkaasti morfiinin kipua lievittävän vasteen opioiditoleranssissa. Se ei kuitenkaan estänyt opioiditoleranssin kehittymistä. Ibudilastin vaikutusmekanismi vaatii lisäselvityksiä. Alfa-2-reseptoreiden estäjä atipametsolia käytetään eläinlääkkeenä anestesian jälkeisessä eläinten herätyksessä. Aivo-selkäydinnesteeseen annettuna atipametsoli lisäsi morfiinin antinosiseptiivista vastetta sekä akuutissa yhteisannossa morfiinin kanssa sekä opioiditoleranssimallissa. Nämä vaikutukset havaittiin hyvin pienillä annoksilla atipametsolia. Nahan alle annosteltuna vastaavaa yhteisvaikutusta morfiinin kanssa ei havaittu. Nesteenpoistolääkkeenä käytetty spironolaktoni lisäsi morfiinin antinosiseptiivista vaikutusta sekä akuutissa yhteisannossa että toleranssimallissa. Pitoisuustutkimuksissa havaittiin spironolaktonin lisäävän morfiinin keskushermostopitoisuuksia. Tämä vaikutus välittyi todennäköisesti lääkeainekuljetusproteiini P-glykoproteiinin estovaikutuksen kautta. Spironolaktoni ei ehkäissyt opioiditoleranssin kehitystä. NMDA-reseptorin estäjä ketamiinin on ajateltu palauttavan opioidien vastetta reseptorien kautta välittyvien farmakodynaamisten yhteisvaikutusten kautta. Lääkkeiden pitoisuusmittauksissa havaittiin, että morfiinitoleranteilla rotilla morfiinin, ketamiinin ja norketamiinin keskushermostopitoisuudet olivat yhteisannossa lisääntyneet huomattavasti verrattuna tilanteeseen, jossa lääkkeitä annettiin yksinään. Ketamiinin hyödyllinen vaikutus opioiditoleranssissa saattaa siis osittain perustua myös farmakokineettiseen yhteisvaikutukseen