1995 — 1996 |
Paronis, Carol A |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Respiration--Relation to Opioid Dependence @ Harvard University (Medical School) |
0.928 |
2014 — 2015 |
Paronis, Carol A. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cannabinoid Dependence Resubmission
DESCRIPTION (provided by applicant): Marijuana is the most commonly used illicit drug in the US, and the emergence of high efficacy synthetic cannabinoid (CB) drugs JWH-018 and JWH073 (sold as Spice and K2) as popularly abused drugs indicate the gravity of the public health challenge posed by CB abuse-related disorders. Cannabis dependence is the third most prevalent substance abuse disorder, after nicotine and alcohol, and 30- 70% of chronic marijuana smokers experience symptoms of CB withdrawal. Despite this, relatively few studies have examined effects of chronically administered CBs in animals. To address this critical gap, we propose to develop robust animal models of CB dependence that can be used to better understand pharmacological and behavioral aspects of CB dependence. A hurdle to modeling CB dependence in animals has been the failure to observe an evident spontaneous withdrawal syndrome; symptoms often are mild and emerge over days. The CB antagonist, rimonabant, has been used to precipitate 'withdrawal', yet it remains unclear whether the effects of rimonabant reflect physical dependence or are the expression of other intrinsic effects of rimonabant. In preliminary studies in mice injected daily with a high efficacy CB1 agonist, AM2389, we found that rimonabant increased paw tremors and disrupted other behaviors; importantly, qualitatively similar results were obtained when the daily agonist injections were interrupted for 24-72 hrs. These data represent the first evidence of spontaneous CB withdrawal in mice and we will systematically extend these studies by delineating the experimental parameters necessary to maximize the expression of CB dependence using radiotelemetry, observation techniques, and operant responding endpoints to measure effects of both spontaneous and precipitated withdrawal. Our first aim is pharmacological, i.e., we will study mice treated chronically with the CB full agonist AM2389, with which we have obtained encouraging preliminary data. Studies will continue in mice treated chronically with the illicit drugs ¿9-tetrahydrocannabinol (THC), or the newly scheduled CBs JWH-018 and JWH-073, anticipating that the intrinsic activity and duration of action for each agonist will determine the magnitude of the observed effects. Our second aim is to identify the role of contextual influences on the development and expression of CB dependence. The importance of contextual cues in maintaining drug- seeking behavior is well-established for other abused substances but has received scant attention in the CB literature. We propose to specifically pair particular environments with injection of rimonabant, and determine if conditioned cues can also 'precipitate' CB withdrawal. Our immediate goals are to identify the pharmacological and behavioral mechanisms underlying the development of CB dependence. The direct impact of these studies will be an increased understanding of consequences of chronic exposure to marijuana and other abused CBs. Our long term goal is to develop a research program in which these models will be used to identify potential new therapies and management strategies for the treatment of cannabis addiction.
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0.958 |
2019 — 2021 |
Paronis, Carol A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Behavioral Pharmacology of Synthetic Cannabinoids
OTHER PROJECT INFORMATION - SECTION 7 - PROJECT SUMMARY/ABSTRACT 1 Increased abuse of designer cannabinoids, such as JWH-018 and AB-PINACA (sold as ?Spice? or ?K2?), 2 continues to be a severe public health concern despite Class I scheduling of these compounds by the DEA. 3 Preclinical studies of these compounds have repeatedly identified them as being THC-like, however 4 occurrences of emesis, hallucinations, seizures, and even death - effects not previously associated with THC 5 or other cannabis products - indicates that there are grave differences between synthetic and plant-derived 6 cannabinoids. We propose to systematically characterize the pharmacological differences among synthetic 7 cannabinoids (SCBs) based on their intrinsic activity in producing CB1 receptor-mediated effects as well as 8 their ability to modulate noncannabinoid effects. The overarching goals of this program are to determine 9 differences between drugs that predict their abuse-related effects and to use these differences to identify 10 useful strategies for acute management of the deleterious effects of designer cannabinoids. These goals will 11 be achieved by addressing three hypotheses: 1) SCBs vary in efficacy at CB1 receptors; 2) SCBs have 12 modulatory effects at other neurotransmitter systems; and 3) differences in the intrinsic activity of SCBs is 13 reflected in their deleterious and reinforcing effects. To address these aims, we propose to use a unique CB1 14 antagonist, AM6538, to temporarily inactivate a portion of CB1 receptors and then assess the ability of a range 15 of SCBs to produce antinociceptive effects or disrupt ongoing behavior. The fraction of receptors remaining for 16 each agonist following AM6538 treatment will vary directly with the intrinsic activity of the SCBs, providing a 17 quantifiable measure of their differences in vivo (apparent ?-value) The second aim of these studies is based 18 on the premise that the hallucinogenic effects of SCBs bear some similarities to the effects of other known 19 hallucinogens, namely LSD, salvinorin A, or ketamine, which are mediated by, respectively, 5-HT2, ?-opioid, or 20 glutamate receptors. To address this aim, drug discrimination procedures will be used to establish assays that 21 can determine the extent to which SCBs have subjective effects similar to those of other hallucinogens. The full 22 or partial substitution profile of the SCBs for the different training drugs is expected to be dependent on the 23 chemical structure of the SCBs or on their intrinsic activity. Lastly, we propose experiments to evaluate the 24 neurocognitive effects and reinforcing effects of SCBs in nonhuman primates in order to identify or clarify the 25 pharmacological relationship that exists between the abuse liability, the hallucinogenic-like profile, and the 26 intrinsic activity of designer cannabinoid drugs. The direct impact of these studies will be to elucidate the 27 relationship between CB1 efficacy and deleterious subjective effects of SCB products. This will aid in 28 characterizing novel drugs as they emerge in the `grey market', and, as well, begin to identify mechanisms by 29 which the effects of these SCBs differ from those of phytocannabiniods.
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0.958 |
2019 — 2021 |
Bergman, Jack (co-PI) [⬀] Paronis, Carol A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
In Vivo Characterization of Opioid Biased Agonists
OTHER PROJECT INFORMATION - SECTION 7 - PROJECT SUMMARY/ABSTRACT 1 The ongoing opioid crisis has led to renewed concerns about the clinical prescription of addictive opioid 2 analgesics. However, there currently are no suitable alternatives for treating severe or malignant pain. Studies 3 of opioid signaling mechanisms in mice lacking the ?-arrestin 2 gene indicate that the acute analgesic effects 4 of morphine were enhanced in these mice, and subsequent studies reported that undesirable effects of 5 morphine including respiratory depression, constipation, and analgesic tolerance were all diminished in the 6 absence of ?-arrestin signaling. These findings have led to increased efforts in developing novel opioid drugs 7 that, based on their preferential activation of G-protein signaling over ?-arrestin signaling in vitro, can be 8 characterized as `biased' agonists. However, although clear distinctions in receptor-activated signaling of 9 opioid ligands are found in vitro, the extent to which these cellular differences predict differing profiles of opioid 10 activity in vivo remains uncertain. Currently, there is not sufficient information to conclude whether biased 11 signaling can indeed be associated with reduced opioid side effects and, consequently, an improved safety 12 profile of `biased' agonists compared to conventional prescription opioids. The present application intends to 13 address the need for preclinical data to rigorous evaluate this possibility with a program of in vivo studies of the 14 effects of novel opioid biased agonists in nonhuman primates. In these studies, we will employ well-established 15 and highly translational pharmacological methods to compare prescription opioids that are `balanced' agonists, 16 i.e., signal through both G-protein and ?-arrestin paths (morphine, oxycodone, and fentanyl) with the `biased' 17 agonist PZM21 and two novel ligands that are provided by colleagues at the NIDA IRP and that, based on in 18 vitro data, also can be characterized as opioid `biased' agonists. First, the acute effects of different opioids will 19 be studied using well-validated assays of antinociception and operant performance, respiratory function, and 20 abuse potential. Data from these studies will enable us to rigorously characterize and compare both the 21 beneficial and unwanted effects of the `balanced' and `biased' agonists. Next, the same drugs will be compared 22 during regimens of chronic treatment. In these studies, assays of antinociception and operant performance will 23 be used to evaluate tolerance, defined by rightward or downward movement of the opioid dose-effect function, 24 and assays of respiratory function and observable behavior to evaluate the presence of opioid dependence, 25 evident as increases in ventilation or characteristic behavioral signs following antagonist administration. The 26 results of the latter studies will provide critical information regarding the dependence liability of `biased' 27 agonists that, in clinical practice, might be given on a repeated, or chronic, basis. Finally, cognizant of sex- 28 related differences in the effects of prescription opioids that are `balanced' agonists, we will conduct our studies 29 in both male and female subjects to determine whether similar sex-related differences are produced by novel 30 opioid `biased' agonists.
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0.958 |