1998 — 1999 |
Neubert, John K |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Mechanisms of Orofacial Neuropathic Pain @ University of California Los Angeles
The goal of this proposed study is to provide the Principal Investigator (P.I.), John K. Neubert, D.D.S., with the opportunity to develop as an independent researcher to complement his clinical training in Orofacial Pain Management. The P.I.'s training will be conducted within the laboratories of the two sponsors of this project, Drs. Kruger and Spigelman, at the UCLA Schools of Medicine and Dentistry. Dr. Neubert's immediate career goals include completion of his Ph.D. in Oral Biology and remaining as an instructor at the UCLA Orofacial Pain Clinic. Long term goals include running a pain research laboratory and establishing an orofacial pain curriculum and clinic at a dental school. The research career development will include further training and experience in the areas of electrophysiology and histology to prepare the P.I. as an independent researcher. Chronic orofacial neuropathic pain (CONP) is a problem of considerable clinical relevance. Understanding the mechanisms underlying orofacial neuropathic pain maintenance becomes an important feature in striving to treat CONP. Experimental evidence from animal studies points to the involvement of inflammatory mediators and tachykinin neuropeptides in the mechanism underlying neuropathic pain. The goals of this study are to characterize the involvement and interactions of inflammatory cytokines and the tachykinin neuropeptide, substance P (SP), in the maintenance of orofacial neuropathic pain. Orofacial neuropathic pain will be induced in an established guinea pig model of trigeminal nerve injury. In vitro intracellular recordings and pharmacological studies and in vivo microdialysis will be utilized as methods for studying SP involvement in CONP. The peripheral involvement of inflammatory cytokines in CONP will be explored with immunohistochemical and light and electron microscopy techniques following trigeminal nerve entrapment. Determination of altered levels of neuropeptides and their interactions with inflammatory mediators, along with changes within the TRIG following neuropathic induction provides a novel, yet important area of investigation for characterizing pain transmission in the trigeminal system.
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1 |
2003 — 2006 |
Neubert, John K |
K22Activity Code Description: To provide support to outstanding newly trained basic or clinical investigators to develop their independent research skills through a two phase program; an initial period involving and intramural appointment at the NIH and a final period of support at an extramural institution. The award is intended to facilitate the establishment of a record of independent research by the investigator in order to sustain or promote a successful research career. |
Molecular Targeting of the Vanilloid-1 Receptor
[unreadable] DESCRIPTION (provided by applicant): The goal of this proposal is to provide the Principal Investigator, John K. Neubert, DDS, PhD, with the opportunity to develop as an independent translational pain researcher. Dr. Neubert has completed a dental residency in orofacial pain management and a PhD in Oral Biology at UCLA and is finishing a clinical research fellowship at the NIH. Additional experience in fundamental molecular and cellular biology is required to provide the principal investigator with the requisite skills needed for this translational research. This experience will be acquired during the Scholar Development Phase and will complement the Principal Investigator's prior in vivo physiological and clinical pain research experiences. This phase will be supervised by Dr. Michael Iadarola at the NIH, who has over 20 years of experience and continues to excel in the areas of molecular and cellular pain biology. Dr. Neubert will receive full institutional support during the Scholar Development Phase from the NIDCR, NIH, including use of facilities, equipment, and support staff. The Faculty Transition Phase will be critical for the principal investigator to become an innovative and independent researcher. [unreadable] [unreadable] Chronic pain continues to affect a countless number of individuals and costs society billions of dollars each year. The vanilloid-1 receptor (VR1) provides an excellent target for analgesia due to its prominent role in inflammation and hyperalgesia. The long-range goal is to investigate the peripheral actions of VR1. The objective is to elucidate the role of VR1 through specific ultrapotent agonists and antagonists designed to induce or block neuronal cells expressing this receptor in vitro, and to evaluate these agents in vivo. The central hypothesis of the proposed research is that peripheral VR1 activity is necessary to effectively transduce painful stimuli. Three Specific Aims will be investigated: Aim #1, Pharmacologically characterize the function of the VR1 -ionophore; Aim #2, Evaluate the analgesic efficacy of vanilloid receptor agonists in models of acute pain; Aim #3, Clinically evaluate the analgesic efficacy of vanilloid receptor agonists for acute and chronic orofacial pain conditions. These aims will be tested by an experimental approach using VRl-transfected cell lines and evaluating their inhibition by chemical compounds screened from combinatorial libraries. Additionally, peripheral application of the potent VR1 agonist, resiniferatoxin (RTX), will be tested in vivo through a number of behavioral and histological assessments to determine if vanilloids are effective in blocking pain. Lastly, RTX will be evaluated for analgesic efficacy in human models of acute and chronic pain. Completion of the proposed studies is expected to provide a better understanding of the mechanisms responsible for contributing to clinical pain, thus leading to development of mechanistically-derived therapies. These outcomes are expected to have significant positive effects on a wide spectrum of pain relating to tissue damage and injury. [unreadable] [unreadable]
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0.964 |
2006 — 2007 |
Neubert, John K |
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.) |
Novel Operant Thermal Assessments of Orofacial Pain
[unreadable] DESCRIPTION (provided by applicant): Orofacial pain encompasses a multitude of disorders, including temporomandibular disorders (TMD), trigeminal neuralgia, headaches (e.g., migraine, tension-type), and myofascial pain, and affects an estimated 20% of the U.S. population. Despite the financial and emotional magnitude of orofacial pain, however, only a limited number of relevant animal models and behavioral assessment techniques have been developed, and relatively few model a human's pain experience and cognitive processing. Our long-range goal is to establish translational models that allow for evaluation of pain within the trigeminal system and to simulate clinical disorders in order to investigate novel analgesic agents. The objective of this particular application is to evaluate operant behavioral assays for assessing trigeminal pain. The central hypothesis for the proposed research is that these operant behavioral assays can provide a sensitive, clinically relevant way to evaluate trigeminal sensory and nociceptive processing. Two specific aims will be investigated: Aim #1, to evaluate an operant model of thermal hyperalgesia and allodynia for evaluating trigeminal nerve mediated pain; and Aim #2, to investigate the effects of opioid and non-opioid mediated analgesia on thermal operant orofacial outcome measures. We will test these aims using an experimental approach using a highly innovative behavioral thermal strategy that involves an operant-conditioning paradigm. This includes: (1) a facial thermal reward-conflict strategy for assessing thermal allodynia and hyperalgesia; and (2) pharmacologic evaluation of the thermal outcome measures. We will use these measures in models of orofacial inflammation, neuropathic pain, and neurogenic inflammation. In these assays, the animal has control over the amount of nociceptive stimuli it will receive and can thus modify its behavior based on a number of factors, including those involving cortical processing. Collectively, these methods will provide noninvasive, quantifiable outcomes of trigeminal pain conditions that better model human experiences. Successful application of these novel behavioral testing strategies will provide a significant advancement in research strategies for understanding mechanisms of orofacial pain disorders. These proposed studies will provide a basis for behavioral studies within the trigeminal system that can be used as a correlate for future studies investigating molecular and physiological markers of pain, thus providing a pivotal link for translating basic pain research into clinic trial strategies. [unreadable] [unreadable]
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0.964 |
2009 — 2010 |
Murphy, Niall P Neubert, John K |
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.) |
Placebos as Insights Into Intersections of Pain and Reward in a Preclinical Model
DESCRIPTION (provided by applicant): The treatment of three particular disorders-pain, depression and Parkinson's disease-is notoriously vulnerable to placebo effects. A striking similarity between these disorders is their dependence on midbrain dopamine and endogenous opioid systems, two neurochemical systems considered fundamental to anticipatory states and addiction. Here, we posit that study of placebo effects offers invaluable insights into how pain, reward, and addiction processes intersect. This is particularly timely, as studies of placebo effects in humans have exploded over the past decade, laying a strong foundation on which to base mechanistic preclinical studies. However, there are virtually no preclinical models of placebo effects of which we are aware. Thus, in Aim 1 we will first establish and validate a preclinical behavioral model of placebo-induced analgesia, based on Pavlovian conditioning to morphine and responding in a novel operant orofacial pain assay. Importantly, this model is able to encompass the cognitive and affective aspects of placebo responses. Second, as stress produces behavioral depression in humans and animals, we will test the hypothesis that a pre-existing pain state attenuates placebo-induced analgesia, based on the rationale that pre-existing pain dampens activity in one of the same neural systems, i.e., dopamine. In Aim 2, we will seek neural correlates of placebo-induced behaviors by simultaneously evaluating dopamine levels in the nucleus accumbens and prefrontal cortex during establishment and expression of placebo- induced analgesia under non-pain and pre-existing pain states. We hypothesize that placebo responses are encoded in midbrain dopamine activity in a similar manner to behaviors typical of drug addiction (e.g., sensitization of mesolimbic dopamine release), and in doing so, we aim to uncover a direct link between the fields of pain, anticipatory behavior, reward, and addiction. Such an understanding is critical to developing novel treatments for pain that avoid addiction, as well developing appropriate strategies for treating pain in addicts and depressed individuals. By combining our specialties in the fields of pain, addiction, and placebo research, we are ideally positioned to develop and complete this line of investigation. PUBLIC HEALTH RELEVANCE: Through these studies, we aim to convincingly demonstrate that animals, like humans, show placebo and nocebo effects. In doing so, we will address the role that these effects have in determining the efficacy of drugs used in the treatment of pain, depression and addiction, in addition to uncovering the associated neurobiology.
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0.964 |
2021 |
Caudle, Robert M (co-PI) [⬀] Neubert, John K |
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. |
Opioid and Cannabinoid Interactions in Pain and Reward
Abstract Chronic pain is a significant public health problem that costs society billions of dollars per year and causes great suffering in countless individuals. Opioid-based medications are among the most prescribed for various forms of chronic pain contributing to the current opioid epidemic. Recently, cannabis and cannabinoid compounds (e.g., ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been described as having pain-alleviating properties. While these cannabinoids, particularly the less psychoactive variant, CBD, may offer alternatives to opioid treatments for pain, few well-controlled studies demonstrate analgesic efficacy, especially for CBD. While it is still unclear if cannabinoids are good stand-alone options for treating pain, cannabinoids may act as useful opioid-sparing drugs, given the substantial overlap between opioid and cannabinoid receptors in reward- and pain-related pathways. Our proposed project will focus on a heuristic approach that incorporates fundamental pharmacology, novel operant behavioral assays of pain, and functional neuroimaging. The long-term goal of this research program is to establish novel approaches to treat chronic pain by maximizing analgesic efficacy and minimizing abuse liability. The objective of this proposal, which embodies the first step toward this long- term goal, is to determine how CBD modifies the effects of oxycodone (OXY), a commonly prescribed opioid analgesic, in the contexts of chronic pain and opioid self-administration. Our overarching hypothesis is that CBD and OXY will act synergistically to yield enhanced analgesic effects, and that CBD will attenuate the effects of pain on OXY self-administration. Two major specific aims will be investigated: (1) to determine how CBD interacts with OXY to reduce chronic operant pain behaviors; and (2) to determine the interacting effects of chronic pain, OXY self-administration, and CBD on analgesia, reinforcement, and dependence. We will assess the effects of preexisting pain on OXY self-administration, as well as the effects of preexisting OXY self- administration on pain. The latter goal is a particularly innovative aspect of this proposal. CBD-modulatory effects on pain and OXY self-administration will be evaluated under both conditions. Neuroimaging will be used across experiments to map and quantify changes in neural connectivity across reward and pain centers of the brain following the various drug treatments (CBD, OXY) and pain states (acute, chronic). Further, we will use clinically important and innovative pain-depressed behavioral assessments that accurately model pain in human subjects. The rationale for completing these studies is that by determining how CBD and OXY interact to affect pain and substance use, we will establish the necessary foundation for future efforts to develop effective analgesics with reduced abuse liability. We believe we are particularly well suited to undertake this project because we have a unified (and already collaborating) multidisciplinary team with complementary expertise in behavioral neuroscience, pharmacology, and neuroimaging.
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0.964 |