Ian D. Meng - US grants

DESCRIPTION (provided by applicant): My main research focus is on the neurophysiological mechanisms underlying the suppression and facilitation of pain. Throughout my years of training, I have tried to develop an integrative approach, relating behavior to the activity of single brain neurons. During the award period, I will work closely with David Bereiter at Rhode Island Hospital and Frank Porreca and Josephine Lai at the University of Arizona on collaborative projects, and will mentor students in my own lab. Long-term, I hope to develop a research program at my university strong enough so that we have the critical mass necessary to secure a self-sustaining and growing network of researchers in the field of pain. Research project: This proposal is focused on the mechanisms of cannabinoid inhibition of nociceptive signals relevant to head and face pain. The medullary dorsal horn receives nociceptive input from orofacial regions, and as the first site of neuronal integration represents a potentially critical target for the antinociceptive actions of cannabinoids. Behavioral experiments have demonstrated that intrathecal administration of a kappa opioid receptor antagonist blocks the antinociceptive effect of intrathecally administered cannabinoids, suggesting that inhibition of nociceptive signals produced by cannabinoid agonists require the release of an endogenous kappa opioid receptor agonist. The proposed experiments will compare the effect of cannabinoids on nociceptive neurons located in superficial versus deep laminae of the medullary dorsal horn. Furthermore, we will determine whether cannabinoids produce inhibition of medullary dorsal horn nociceptive neurons indirectly by stimulating the release of an endogenous kappa opioid receptor agonist. Using extracellular electrophysiological single unit recordings, we will compare the effect of cannabinoid receptor agonists applied directly to the medullary dorsal horn (bath application) on the activity of superficial and deep nociceptive neurons. Neuronal activity will be evoked by thermal stimulation of the receptive field. To determine whether cannabinoids indirectly modulate neuronal activity by inducing the release of an endogenous kappa opioid receptor agonist, cannabinoids will be tested in the presence of a kappa opioid receptor antagonist. The long-term objective of this research is to increase our understanding of the neuropharmacological mechanisms underlying cannabinoid-induced suppression of trigeminal pain and ultimately determine whether cannabinoids may be a useful class of medication for trigeminal pain patients as either a primary or adjuvant therapy.

[unreadable] DESCRIPTION (provided by applicant): Medication overuse headache (MOH) is a chronic daily headache that develops from the frequent use of medications taken for the treatment of migraine headache pain. Despite its clinical significance, the underlying mechanisms of MOH remain unknown. We hypothesize that chronic use of analgesics leads to neuro-adaptive changes in the nervous system that causes an increase in the excitability of neurons involved in headache pain. Although several studies have provided indirect evidence for chronic morphine-induced sensitization of nociceptive signals, direct electrophysiological evidence is lacking. Using extracellular single unit recordings, the proposed experiments will examine the effects of sustained morphine administration in rats on the properties of spinal trigeminal nucleus (Vsp) neurons relevant to headache pain. We will test the hypothesis that sustained morphine administration up-regulates pronociceptive systems, as indicated by an increase in the excitability of dura sensitive Vsp neurons (Aim 1). Additional experiments will test the hypothesis that descending facilitation from the rostral ventromedial medulla (RVM) is necessary for the increased excitability of Vsp dura sensitive neurons following sustained morphine exposure (Aim 2). As part of these aims we will also test the hypothesis that chronic morphine induced increases in descending facilitation from the RVM interferes with counter-irritation, as defined by the inhibition of dura sensitive neurons produced by the application of a remote noxious stimulus. Significantly, patients with chronic daily headache have been shown to lack the normal inhibition of pain produced by counter-irritation. The overall goal of this research is to study how chronic drug exposure can produce neuro-adaptive changes in dura sensitive neurons that may lead to an increased frequency of headaches. Medication overuse headache represents a major clinical problem, affecting 1-2 percent of the general population, and can be caused by overuse of opiates, triptans and "over-the-counter" analgesics. The proposed experiments will provide insight into how sustained morphine exposure can modulate headache-related neural pathways. Understanding the neuro-adaptive changes that occur with chronic morphine exposure will lead the way to new therapeutic strategies to treat headache patients while reducing the risk of developing MOH. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Dry eye syndrome (DES) results from an inadequate tear film on the corneal surface. As a result, patients with DES suffer from ocular pain and in some cases serious vision problems. DES affects as much as 20% of the population and treatment often remains inadequate. One cause of dry eye may be an inability of sensory neurons to properly assess the ocular surface fluid status by responding to drying of the cornea. The neural regulatory mechanisms involved in maintaining a normal tear-film, via basal tear production, are still unknown. We have recently discovered that a class of corneal primary afferent neurons, cold cells, which are known to respond to non-noxious cooling, are also activated by drying of the ocular surface, hyperosmotic solutions, and menthol. These properties would be expected of neurons that participate in the regulation of basal tearing, as evaporation of tears from the corneal surface causes both cooling and increased osmolarity of the tear film. It is hypothesized that these dry-responsive cold cells represent the afferent limb of the reflex arc that drives non- noxious basal tearing without producing ocular pain. This hypothesis will be examined in four specific aims. The first aim will determine the encoding properties of corneal primary afferent neurons activated by drying of the ocular surface. A particular focus will be on hyperosmotic and TRPM8 dependent evoked responses;TRPM8 channels are activated by both menthol and innocuous cooling. Corneal primary afferents will be characterized using in vivo single-unit electrophysiology in the rat trigeminal ganglion. Responses to drying of the ocular surface will be examined, as well as responses evoked by thermal, chemical, and osmotic stimuli. Aim 2 will determine the ability of TRPM8 agonists to alter cold- and dry-evoked responses in corneal primary afferent neurons. Aim 3 will determine the encoding properties and projection targets of spinal trigeminal nucleus (Vsp) neurons activated by drying of the ocular surface. Single unit recordings in Vsp will be used to assess properties of neurons that receive direct input from corneal primary afferents, and electrical stimulation will be employed to test for their projection status to regions involved in the regulation of tearing. Finally, Aim 4 will determine the circuitry within the spinal trigeminal nucleus involved in lacrimation and nocifensive behaviors evoked by TRPM8 and TRPA1 agonists applied to the ocular surface in rats. Lesions in two distinct regions of Vsp that receive corneal inputs will be performed to determine their relative contribution to tearing and nocifensive responses to ocular stimulation. The ability to increase the sensitivity and activity of neurons that respond to drying of the ocular surface represents a novel strategy for the potential treatment of DES. PUBLIC HEALTH RELEVANCE: Dry eye syndrome (DES), which affects as much as 20% of the population, causes feelings of discomfort and pain and can lead to serious vision problems. Treatment for DES often remains inadequate. The proposed research examines the ability of specific sensory neurons to increase tearing without producing pain. This line of research could lead the way to new methods for treating DES.

The Administrative Core is essential to the Center's success, responsible for the coordination and execution of the mentorship and career development plan for COBRE Project Leaders. In performing this function, the Administrative Core will monitor research progress, and assess the goals and accomplishments of COBRE investigators to ensure that they are on track to attain independent investigator status. It will provide administrative support for COBRE investigators, listen and respond to their needs, and, with the help of the Internal Advisory Committee (lAC), advocate for these needs within the institution. It will coordinate the function and capabilities of the Imaging and Behavioral Cores so that they meet the evolving needs of the COBRE investigators. It will communicate with the grants administrator to provide assistance to COBRE investigators in finding and applying for external funding. It will organize bimonthly meetings of COBRE investigators to share data and to identify potential areas for internal collaboration and synergy. The Administrative Core is also responsible for leading the review process for the COBRE pilot grants program and for faculty recruitment efforts. The Administrative Core will organize COBRE sponsored symposia that will be coordinated with the semi-annual external advisory committee (EAC) meetings. These symposia will offer COBRE investigators a chance to present and receive feedback on their own research findings, as well as an opportunity for them to interact with and hear presentations from leading pain researchers outside the institution. Finally, the Administrative Core will be responsible for the fiscal management of the Center and lead the assessment of all COBRE programs to ensure accomplishment of the Center's long-term goals.

Treatment of chronic pain continues to rely on old drugs such as gabapentinoids, reuptake blockers and opioids, all of which have severe side effects that diminish quality of life. Tolerance develops to opioids with chronic use, and an increase in opioid prescriptions has contributed to the growing opioid addiction epidemic. There is an urgent need for finding alternative treatments for treatment of both acute chronic pain. The goal of the COBRE Phase II is to continue the development of a Center for the Study of Pain and Sensory Function that will significantly contribute to the scientific understanding of the neurobiology of acute and chronic pain, facilitating the discovery of novel therapies. Significant progress was made during Phase I: four project leaders were successful in receiving NIH support and three COBRE pilot project grants seeded studies that subsequently received extramural support. Targets for recruitment were exceeded with the addition of both senior and junior faculty members to our Center. Two research cores were established and new lab space was created through renovations. The Center will continue to build on these accomplishments, leveraging COBRE support to garner additional institutional investment in the program. Our research cores will continue to collaborate with those at other regional IDeA program funded institutions, efficiently utilizing our resources as we work towards increased sustainability. Specific Aim 1 will create a critical mass of pain researchers necessary to sustain a vibrant research center and enhance their ability to compete for extramural research support. This Aim will be accomplished by fostering the pain related research programs of four current UNE faculty members who have not received R01 or comparable Research Project Grant support. In addition, funds will be provided for pilot projects to support early stage yet innovative pain-related studies. Finally, we will recruit an additional three investigators whose research programs will complement those of the existing faculty. Specific Aim 2 will expand neuroscience research infrastructure at UNE, providing access to core facilities that allow investigators to carry out cutting edge research on the neurobiological processes involved in the development of chronic pain. This aim will be accomplished through funding key support personnel and the purchase of equipment for the two research cores established during Phase I (the Behavior Core and the Histology and Imaging Core). Expanded research core services will include mouse genotyping and expert consultations for breeding strategies required for maintaining transgenic mouse colonies (Behavior Core), and a service to validate antibodies used by COBRE center researchers (Histology and Imaging Core). With continued investment provided through Phase II funding and institutional support, we will build on our early success and clearly establish the Center as a leader in pain research.

Dry eye disease results from an inadequate tear film on the corneal surface that can result in ocular pain and in some cases serious vision problems. Symptoms of dry eye disease are a primary reason for patient visits to ophthalmologists and optometrists in the United States, and for many sufferers treatment remains inadequate. Previous studies demonstrate a clear role for corneal primary afferent neurons in maintaining the corneal epithelium under normal conditions, presumably through the release of factors that prevent epithelial cell apoptosis and stimulate proliferation. However, the role of these sensory neurons in supporting corneal healing under pathological conditions such as dry eye remains unknown. We hypothesize that dry eye disease and its associated corneal damage initiates an injury-response program in corneal afferent neurons that involves the upregulation of nerve regeneration-associated genes, such as the transcription factor Sox11, in the trigeminal ganglion. It is proposed that upregulation of Sox11 in dry eye is critical for maintaining corneal afferent innervation and thus maintaining the trophic support required to promote corneal healing. The aims in this proposal explore the impact of Sox11 expression in the trigeminal ganglion and the role it plays in maintaining corneal afferent innervation and promoting corneal healing in dry eye. Aim 1 will examine the expression of Sox11 and its downstream gene targets in corneal afferent cell bodies of the trigeminal ganglion following induction of dry eye by lacrimal gland excision. Aim 2 will determine the role of Sox11 in maintaining corneal innervation and sensitivity in dry eye, utilizing a transgenic mouse line in which Sox11 is deleted only in small diameter sensory fibers (including corneal primary afferent neurons). The contribution of Sox11 in these neurons to corneal nerve morphology and functional sensitivity will be examined following lacrimal gland excision. Using these same mice, Aim 3 will determine how deletion of Sox11 in corneal primary afferent neurons impacts the condition of the corneal epithelium following lacrimal gland excision. Corneal fluorescein staining and epithelial cell proliferation and apoptosis will be examined. Finally, Aim 4 will utilize a viral vector to drive the overexpression Sox11 in small diameter sensory fibers, including the corneal afferent neurons, to determine if increasing expression of Sox11 in these neurons can further promote or improve corneal healing under dry eye conditions. The proposed studies will elucidate novel mechanisms that, if targeted appropriately, could simultaneously maintain corneal innervation and facilitate corneal healing in patients suffering from dry eye disease.

The Administrative Core is a central component of the COBRE and critical to its overall success. Led by the COBRE Director, the Administrative Core executes the mentorship and career development plans of its project leaders, sets benchmarks for success, monitors research progress, and assesses the performance of the research cores. Close communication with the external advisory committee (EAC) provides general programmatic advice to the COBRE Director and timely feedback to the project leaders. The EAC also evaluates and recommends pilot project proposals for COBRE funding. The internal advisory committee, which includes top university administrative officials, ensures continued institutional support for the program and facilitates the removal of any institutional barriers that might impede the Center?s success. Specific Aim 1 is to coordinate and execute the mentorship plan for COBRE project leaders. A mentorship team, with the assistance of a highly engaged EAC, ensures that COBRE investigators receive the necessary scientific and career development advice for attaining independent investigator status. Clear milestones are defined and progress is evaluated. Specific Aim 2 is to administer the pilot project grant program. Annual solicitations for pilot project proposals will be made, and projects will be reviewed by the EAC and COBRE Director. Pilot project grant recipients will receive mentorship similar to COBRE project leaders, and will undergo an annual research performance review. Specific Aim 3 is to lead the recruitment and hiring processes. We will recruit faculty with clinical pain research experience in Physical Therapy and Dental Medicine, as well as an Associate Dean for Research for the College of Osteopathic Medicine. Specific Aim 4 is to oversee fiscal management and evaluate center progress in order to ensure that the center is on track for meeting its overall goals. The Administrative Core will conduct annual evaluations of the research cores and investigators. Action plans in response to these evaluations will be implemented to ensure that investigators remain on track for manuscript and grant submissions, and that each of the research cores remains responsive to the needs of their users. An effective Administrative Core unifies the Center as it responds to the needs of its constituents. The Administrative Core will continue to support the careers of COBRE investigators and coordinate the development of research infrastructure that has already significantly transformed the University. Moreover, in COBRE Phase II, we will deepen our collaborations with other regional COBREs and the Maine INBRE.