MECHANISMS OF PERSISTENT TEMPOROMANDIBULAR PAIN
Ke Ren, Professor
University Of Maryland Baltimore, 620 W Lexington St, 4th Fl, Baltimore, Md 21201-1508
Grant 5R01DE011964-12 from National Institute Of Dental & Craniofacial Research
Abstract: Painful temporomandibular joint disorders (TMJO) involve deep tissues including muscle and joint. The etiology and pathology of these disorders remain unclear. This project has been dedicated to developing animal models of deep pain in the craniomandibular region and pursuing studies of the function of the trigeminal brainstem sensory nuclei arid surrounding structures in persistent inflammatory pain conditions. We have demonstrated that masseter inflammation activated distinct regions in the spinal trigeminal nucleus (Vsp), the subnucleus interpolaris/caudalis transition zone (Vi/Vc) and the more caudal laminated subnucleus caudalis contiguous with the upper cervical dorsal horn (Vc/Ci,2). Further, the Vi/Vc transition zone plays an important role in the processing of orofacial inputs related to deep tissue injury. In light of our previous findings and recent developments on neuronal plasticity and persistent pain, we propose to extend our studies by further identifying the cellular and molecular mechanisms of the trigeminal processing of deep orofacial input after inflammation in the next grant period with an emphasis on neuronal-glial interactions. Our major hypotheses are that 1) orofacial deep tissue injury induces neuronal plasticity in the ViA/c transition zone of the Vsp through activation of glia and 2) ViA/c glial activation and inflammatory cytokine release affect or facilitate neuronal plasticity through interactions with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These hypotheses will be tested in rat models of tissue injury and plasticity by a combination of approaches involving immunohistochemistry, immunoprecipitation, Western blot, behavior testing and the neuropharmacological method. Aim 1 will test the hypothesis that glial cells are activated in the ViA/c of Vsp after masseter inflammation and affect neuronal function through release of inflammatory cytokines. Aim 2 will determine whether primary afferent input plays a role in glial activation after orofacial inflammation. Aim 3 will test the hypothesis that ViA/c glial activation and associated cytokine release facilitate neuron plasticity through interaction with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These studies will elucidate the significance of glial-cytokine-neuronal interactions in the development of orofacial hyperalgesia and further establish the importance of the trigeminal transition zone in response to orofacial deep injury. The findings will advance our understanding of the mechanisms of persistent pain associated with TMJD and facilitate the designing of new therapeutic approaches
Keywords: Abscission; Address; Affect; Afferent Neurons; Animal Model; Animal Models and Related Studies; Articulation; Behavioral; Blotting, Western; Body Tissues; Brain Stem; Brainstem; CNS plasticity; Cachectin; Cachectin-Tumor Necrosis Factor; Causality; Cell Communication and Signaling; Cell Nucleus; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cervical; Chemicals; Clinical Management; Common Rat Strains; Communicating Junction; Development; Disease; Disorder; Electric Stimulation; Electrical Stimulation; Etiology; Event; Excision; Extirpation; Freund`s Adjuvant; Freund`s Complete Adjuvant; Funding; Gap Junctions; Glia; Glial Cells; Glutamate Receptor; Goals; Grant; Hortega cell; Hyperalgesia; Hyperalgesic Sensations; IHC; IL-1 inhibitor, urine; IL-1ra; IL1 febrile inhibitor; IL1RN; INFLM; Immune Precipitation; Immunohistochemistry; Immunohistochemistry Staining Method; Immunoprecipitation; Immunostimulants, adjuvants, Freund`s; Inferior Maxillary Bone; Inflammation; Inflammatory; Injury; Interleukin-1 Receptor Antagonist; Interleukins; Intracellular Communication and Signaling; Investigators; Jaw Joint; Joints; Kolliker`s reticulum; Lead; Light; Literature; Local anesthesia; Low-resistance Junction; Magnesium; Maintenance; Maintenances; Mammals, Rats; Mandible; Mandibular joint; Mediator; Mediator of Activation; Mediator of activation protein; Methods; Mg element; Microglia; Modeling; Molecular; Muscle; Muscle Tissue; NK-1 Receptors; NK1R; NKIR; Nerve; Nerve Cells; Nerve Unit; Nervous; Neural Cell; Neurocyte; Neuroglia; Neuroglial Cells; Neuronal Plasticity; Neurons; Neurons, Afferent; Neurons, Sensory; Nexus; Nexus Junction; Non-neuronal cell; Nucleus; Nucleus of the Spinal Tract of the Trigeminal Nerve; Outcome; Pain; Painful; Pathology; Pb element; Peripheral; Persistent pain; Phosphorylation; Photoradiation; Play; Post-Translational Regulation; Posttranslational Regulation; Principal Investigator; Process; Programs (PT); Programs [Publication Type]; Protein Phosphorylation; Rat; Rattus; Receptor Protein; Receptors, Neurokinin-1; Removal; Research Personnel; Researchers; Role; SP-P Receptors; Sensory; Sensory Cell Afferent Neuron; Series; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skin; Staging; Structure; Structure of trigeminal nerve spinal tract nucleus; Substance P Receptor; Surgical Removal; Synapses; Synaptic; TAC1R; TACR1; TMJ; TMJ Diseases; TMJ Disorders; TMJD; TNF (unspecified); TNF Receptor Ligands; TNF-alpha; Tachykinin Receptor 1; Temporo-mandibular joint disorder; Temporomandibular Disorders; Temporomandibular Joint; Temporomandibular Joint Diseases; Temporomandibular Joint Disorders; Temporomandibular joint disorder; Testing; Time; Tissue Model; Tissues; Trigeminal Nucleus, Spinal; Trigeminal System; Tumor Necrosis Factor; Tumor Necrosis Factor Family Protein; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; V (voltage); Western Blotting; Western Blottings; Western Immunoblotting; Work; Yang; active control; anakinra; behavior test; behavioral test; biological signal transduction; central sensitization; chemical release; chronic pain; chronic painful condition; cytokine; design; designing; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; dorsal horn; experiment; experimental research; experimental study; gitter cell; heavy metal Pb; heavy metal lead; hyperalgia; inflammatory pain; inhibitor; inhibitor/antagonist; interleukin 1 inhibitor, urine; interleukin 1 receptor antagonist protein; lower sensory nucleus of trigeminal nerve; mandibular; mesoglia; microglial cell; microgliocyte; model organism; nerve cement; neural circuit; neural circuitry; neural plasticity; neuronal; neuropathic pain; neuroplasticity; novel; novel therapeutic intervention; orofacial; painful neuropathy; perivascular glial cell; programs; protein blotting; receptor; research study; resection; response; social role; temporomandibular pain; trigeminal; tumor necrosis factor (unspecified); unspecified interleukin; urine-derived IL1 inhibitor; voltage
Project start date: 1996-09-15
Project end date: 2012-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
5R01DE011964-12 (2009): $359749
Sponsored Links Excellgen http://Excellgen.com
MECHANISMS OF PERSISTENT TEMPOROMANDIBULAR PAIN
Ke Ren, Professor
University Of Maryland Baltimore, 620 W Lexington St, 4th Fl, Baltimore, Md 21201-1508
Grant 5R01DE011964-13 from National Institute Of Dental & Craniofacial Research
Abstract: Painful temporomandibular joint disorders (TMJO) involve deep tissues including muscle and joint. The etiology and pathology of these disorders remain unclear. This project has been dedicated to developing animal models of deep pain in the craniomandibular region and pursuing studies of the function of the trigeminal brainstem sensory nuclei arid surrounding structures in persistent inflammatory pain conditions. We have demonstrated that masseter inflammation activated distinct regions in the spinal trigeminal nucleus (Vsp), the subnucleus interpolaris/caudalis transition zone (Vi/Vc) and the more caudal laminated subnucleus caudalis contiguous with the upper cervical dorsal horn (Vc/Ci,2). Further, the Vi/Vc transition zone plays an important role in the processing of orofacial inputs related to deep tissue injury. In light of our previous findings and recent developments on neuronal plasticity and persistent pain, we propose to extend our studies by further identifying the cellular and molecular mechanisms of the trigeminal processing of deep orofacial input after inflammation in the next grant period with an emphasis on neuronal-glial interactions. Our major hypotheses are that 1) orofacial deep tissue injury induces neuronal plasticity in the ViA/c transition zone of the Vsp through activation of glia and 2) ViA/c glial activation and inflammatory cytokine release affect or facilitate neuronal plasticity through interactions with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These hypotheses will be tested in rat models of tissue injury and plasticity by a combination of approaches involving immunohistochemistry, immunoprecipitation, Western blot, behavior testing and the neuropharmacological method. Aim 1 will test the hypothesis that glial cells are activated in the ViA/c of Vsp after masseter inflammation and affect neuronal function through release of inflammatory cytokines. Aim 2 will determine whether primary afferent input plays a role in glial activation after orofacial inflammation. Aim 3 will test the hypothesis that ViA/c glial activation and associated cytokine release facilitate neuron plasticity through interaction with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These studies will elucidate the significance of glial-cytokine-neuronal interactions in the development of orofacial hyperalgesia and further establish the importance of the trigeminal transition zone in response to orofacial deep injury. The findings will advance our understanding of the mechanisms of persistent pain associated with TMJD and facilitate the designing of new therapeutic approaches
Keywords: Abscission; Address; Affect; Afferent Neurons; Animal Model; Animal Models and Related Studies; Articulation; Behavioral; Blotting, Western; Body Tissues; Brain Stem; Brainstem; CNS plasticity; Cachectin; Cachectin-Tumor Necrosis Factor; Causality; Cell Communication and Signaling; Cell Nucleus; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cervical; Chemicals; Clinical Management; Common Rat Strains; Communicating Junction; Development; Disease; Disorder; Electric Stimulation; Electrical Stimulation; Etiology; Event; Excision; Extirpation; Freund`s Adjuvant; Freund`s Complete Adjuvant; Funding; Gap Junctions; Glia; Glial Cells; Glutamate Receptor; Goals; Grant; Hortega cell; Hyperalgesia; Hyperalgesic Sensations; IHC; IL-1 inhibitor, urine; IL-1ra; IL1 febrile inhibitor; IL1RN; INFLM; Immune Precipitation; Immunohistochemistry; Immunohistochemistry Staining Method; Immunoprecipitation; Immunostimulants, adjuvants, Freund`s; Inferior Maxillary Bone; Inflammation; Inflammatory; Injury; Interleukin-1 Receptor Antagonist; Interleukins; Intracellular Communication and Signaling; Investigators; Jaw Joint; Joints; Kolliker`s reticulum; Lead; Light; Literature; Local anesthesia; Low-resistance Junction; Magnesium; Maintenance; Maintenances; Mammals, Rats; Mandible; Mandibular joint; Mediator; Mediator of Activation; Mediator of activation protein; Methods; Mg element; Microglia; Modeling; Molecular; Muscle; Muscle Tissue; NK-1 Receptors; NK1R; NKIR; Nerve; Nerve Cells; Nerve Unit; Nervous; Neural Cell; Neurocyte; Neuroglia; Neuroglial Cells; Neuronal Plasticity; Neurons; Neurons, Afferent; Neurons, Sensory; Nexus; Nexus Junction; Non-neuronal cell; Nucleus; Nucleus of the Spinal Tract of the Trigeminal Nerve; Outcome; Pain; Painful; Pathology; Pb element; Peripheral; Persistent pain; Phosphorylation; Photoradiation; Play; Post-Translational Regulation; Posttranslational Regulation; Principal Investigator; Process; Programs (PT); Programs [Publication Type]; Protein Phosphorylation; Rat; Rattus; Receptor Protein; Receptors, Neurokinin-1; Removal; Research Personnel; Researchers; Role; SP-P Receptors; Sensory; Sensory Cell Afferent Neuron; Series; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skin; Staging; Structure; Structure of trigeminal nerve spinal tract nucleus; Substance P Receptor; Surgical Removal; Synapses; Synaptic; TAC1R; TACR1; TMJ; TMJ Diseases; TMJ Disorders; TMJD; TNF (unspecified); TNF Receptor Ligands; TNF-alpha; Tachykinin Receptor 1; Temporo-mandibular joint disorder; Temporomandibular Disorders; Temporomandibular Joint; Temporomandibular Joint Diseases; Temporomandibular Joint Disorders; Temporomandibular joint disorder; Testing; Time; Tissue Model; Tissues; Trigeminal Nucleus, Spinal; Trigeminal System; Tumor Necrosis Factor; Tumor Necrosis Factor Family Protein; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; V (voltage); Western Blotting; Western Blottings; Western Immunoblotting; Work; Yang; active control; anakinra; behavior test; behavioral test; biological signal transduction; central sensitization; chemical release; chronic pain; chronic painful condition; cytokine; design; designing; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; dorsal horn; experiment; experimental research; experimental study; gitter cell; heavy metal Pb; heavy metal lead; hyperalgia; inflammatory pain; inhibitor; inhibitor/antagonist; interleukin 1 inhibitor, urine; interleukin 1 receptor antagonist protein; lower sensory nucleus of trigeminal nerve; mandibular; mesoglia; microglial cell; microgliocyte; model organism; nerve cement; neural circuit; neural circuitry; neural plasticity; neuronal; neuropathic pain; neuroplasticity; novel; novel therapeutic intervention; orofacial; painful neuropathy; perivascular glial cell; programs; protein blotting; receptor; research study; resection; response; social role; temporomandibular pain; trigeminal; tumor necrosis factor (unspecified); unspecified interleukin; urine-derived IL1 inhibitor; voltage
Project start date: 1996-09-15
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
5R01DE011964-13 (2010): $356151
5R01DE011964-11 (2008): $359749
5R01DE011964-04 (1999): $223420
5R01DE011964-03 (1998): $218423
5R01DE011964-02 (1997): $223039
5R01DE011964-09 (2005): $331767
5R01DE011964-08 (2004): $331835
5R01DE011964-07 (2003): $331902
5R01DE011964-06 (2002): $298554
Grants awarded to Ke Ren
Cytokine Pathways And Orofacial Pain
Ke Ren, Associate Professor
University Of Maryland Baltimore 660 W Redwood St, Rm 021 Baltimore, Md 21201
Grant 5R01DE015374-04 from National Institute Of Dental And Craniofacial Research IRG: ZDE1
Abstract: Temporomandibular joint disorders (TMJDs), affect the musculoskeletal and joint tissues, are heterogeneous in origin, and are often not successfully treated. The etiology and pathology of these disorders remain unclear. Recent studies indicate that proinflammatory cytokines are associated with responses of the nervous system to tissue or nerve injury. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-l beta (IL-l beta) are released at the site of injury and contribute to an increased sensitivity of peripheral nociceptors. Importantly, the involvement of cytokines in persistent pain does not appear to be limited to peripheral sensitization. Intefleukin-l beta induces cyclooxygenase-2 (Cox-2) in the CNS. The activation of Cox-2 leads to central prostanoid production and may underlie the mechanisms of centrally mediated pain involving muscle and joint. Interestingly, inflammatory hyperalgesia is apparently mediated through an endogenous pain facilitatory pathway involving rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. Few studies have directly addressed the role of proinflammatory cytokines in orofacial pain mechanisms, despite the findings that some cytokines are found in the synovial fluid of arthritic but not in healthy TMJs. Here we propose to use a rat model of irritant-induced hyperalgesiaJallodynia to investigate the contribution of peripheral and central cytokine pathways to persistent orofacial pain. Our major hypotheses are 1) cytokines and related pathways are activated after orofacial inflammation and play a critical role in the development of persistent hyperalgesia/allodynia and 2) the hyperalgesic effect of cytokines involves an interaction with central pain descending modulatory circuitry. Aim 1 will characterize the development of orofacial hyperaIgesia/allodynia induced by inflammatory irritants. Aim 2 will investigate the activation of cytokines and related pathways in the CNS after injection of inflammatory irritants into the masseter. Aim 3 will evaluate the effects of the inhibitors of cytokine and related Cox pathways on masseter hyperalgesia/allodynia. Aim 4 will examine the interaction of the pain descending modulatory circuitry and trigeminal pathways in cytokine-induced orofacial inflammatory hypersensitivity. In summary, we propose a set of experiments to examine the involvement of the cytokine cascade in persistent orofacial pain mechanisms. The findings will further our understanding of the etiology and pathology of muscle-related TMJDs and facilitate the search for novel and efficient I approaches for the management of persistent orofacial pain.
Keywords: cytokine, disease /disorder etiology, oral facial pain, pathologic process, enzyme mechanism, gene expression, hyperalgesia, inflammation, interleukin 1, interleukin 6, irritation /irritant, neuroanatomy, neuropharmacology, prostaglandin endoperoxide synthase, spinal trigeminal nucleus, striated muscle, temporomandibular joint syndrome, tumor necrosis factor alpha, Freund s adjuvant, behavior test, immunocytochemistry, laboratory rat
Project start date: 2003-08-01
Project end date: 2008-07-31
5R01DE015374-04 (2006): $326274
5R01DE015374-03 (2005): $334125
5R01DE015374-02 (2004): $334125
1R01DE015374-01 (2003): $334125
MECHANISMS OF PERSISTENT TEMPOROMANDIBULAR PAIN
Ke Ren, Professor
University Of Maryland Baltimore, 620 W Lexington St, 4th Fl, Baltimore, Md 21201-1508
Grant 3R01DE011964-12S1 from National Institute Of Dental & Craniofacial Research
Abstract: Painful temporomandibular joint disorders (TMJO) involve deep tissues including muscle and joint. The etiology and pathology of these disorders remain unclear. This project has been dedicated to developing animal models of deep pain in the craniomandibular region and pursuing studies of the function of the trigeminal brainstem sensory nuclei arid surrounding structures in persistent inflammatory pain conditions. We have demonstrated that masseter inflammation activated distinct regions in the spinal trigeminal nucleus (Vsp), the subnucleus interpolaris/caudalis transition zone (Vi/Vc) and the more caudal laminated subnucleus caudalis contiguous with the upper cervical dorsal horn (Vc/Ci,2). Further, the Vi/Vc transition zone plays an important role in the processing of orofacial inputs related to deep tissue injury. In light of our previous findings and recent developments on neuronal plasticity and persistent pain, we propose to extend our studies by further identifying the cellular and molecular mechanisms of the trigeminal processing of deep orofacial input after inflammation in the next grant period with an emphasis on neuronal-glial interactions. Our major hypotheses are that 1) orofacial deep tissue injury induces neuronal plasticity in the ViA/c transition zone of the Vsp through activation of glia and 2) ViA/c glial activation and inflammatory cytokine release affect or facilitate neuronal plasticity through interactions with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These hypotheses will be tested in rat models of tissue injury and plasticity by a combination of approaches involving immunohistochemistry, immunoprecipitation, Western blot, behavior testing and the neuropharmacological method. Aim 1 will test the hypothesis that glial cells are activated in the ViA/c of Vsp after masseter inflammation and affect neuronal function through release of inflammatory cytokines. Aim 2 will determine whether primary afferent input plays a role in glial activation after orofacial inflammation. Aim 3 will test the hypothesis that ViA/c glial activation and associated cytokine release facilitate neuron plasticity through interaction with neuronal glutamate receptors and play a critical role in the development of inflammatory hyperalgesia. These studies will elucidate the significance of glial-cytokine-neuronal interactions in the development of orofacial hyperalgesia and further establish the importance of the trigeminal transition zone in response to orofacial deep injury. The findings will advance our understanding of the mechanisms of persistent pain associated with TMJD and facilitate the designing of new therapeutic approaches
Keywords: Abscission; Address; Affect; Afferent Neurons; Animal Model; Animal Models and Related Studies; Articulation; Behavioral; Blotting, Western; Body Tissues; Brain Stem; Brainstem; CNS plasticity; Cachectin; Cachectin-Tumor Necrosis Factor; Causality; Cell Communication and Signaling; Cell Nucleus; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cervical; Chemicals; Clinical Management; Common Rat Strains; Communicating Junction; Development; Disease; Disorder; Electric Stimulation; Electrical Stimulation; Etiology; Event; Excision; Extirpation; Freund`s Adjuvant; Freund`s Complete Adjuvant; Funding; Gap Junctions; Glia; Glial Cells; Glutamate Receptor; Goals; Grant; Hortega cell; Hyperalgesia; Hyperalgesic Sensations; IHC; IL-1 inhibitor, urine; IL-1ra; IL1 febrile inhibitor; IL1RN; INFLM; Immune Precipitation; Immunohistochemistry; Immunohistochemistry Staining Method; Immunoprecipitation; Immunostimulants, adjuvants, Freund`s; Inferior Maxillary Bone; Inflammation; Inflammatory; Injury; Interleukin-1 Receptor Antagonist; Interleukins; Intracellular Communication and Signaling; Investigators; Jaw Joint; Joints; Kolliker`s reticulum; Lead; Light; Literature; Local anesthesia; Low-resistance Junction; Magnesium; Maintenance; Maintenances; Mammals, Rats; Mandible; Mandibular joint; Mediator; Mediator of Activation; Mediator of activation protein; Methods; Mg element; Microglia; Modeling; Molecular; Muscle; Muscle Tissue; NK-1 Receptors; NK1R; NKIR; Nerve; Nerve Cells; Nerve Unit; Nervous; Neural Cell; Neurocyte; Neuroglia; Neuroglial Cells; Neuronal Plasticity; Neurons; Neurons, Afferent; Neurons, Sensory; Nexus; Nexus Junction; Non-neuronal cell; Nucleus; Nucleus of the Spinal Tract of the Trigeminal Nerve; Outcome; Pain; Painful; Pathology; Pb element; Peripheral; Persistent pain; Phosphorylation; Photoradiation; Play; Post-Translational Regulation; Posttranslational Regulation; Principal Investigator; Process; Programs (PT); Programs [Publication Type]; Protein Phosphorylation; Rat; Rattus; Receptor Protein; Receptors, Neurokinin-1; Removal; Research Personnel; Researchers; Role; SP-P Receptors; Sensory; Sensory Cell Afferent Neuron; Series; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skin; Staging; Structure; Structure of trigeminal nerve spinal tract nucleus; Substance P Receptor; Surgical Removal; Synapses; Synaptic; TAC1R; TACR1; TMJ; TMJ Diseases; TMJ Disorders; TMJD; TNF (unspecified); TNF Receptor Ligands; TNF-alpha; Tachykinin Receptor 1; Temporo-mandibular joint disorder; Temporomandibular Disorders; Temporomandibular Joint; Temporomandibular Joint Diseases; Temporomandibular Joint Disorders; Temporomandibular joint disorder; Testing; Time; Tissue Model; Tissues; Trigeminal Nucleus, Spinal; Trigeminal System; Tumor Necrosis Factor; Tumor Necrosis Factor Family Protein; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; V (voltage); Western Blotting; Western Blottings; Western Immunoblotting; Work; Yang; active control; anakinra; behavior test; behavioral test; biological signal transduction; central sensitization; chemical release; chronic pain; chronic painful condition; cytokine; design; designing; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; dorsal horn; experiment; experimental research; experimental study; gitter cell; heavy metal Pb; heavy metal lead; hyperalgia; inflammatory pain; inhibitor; inhibitor/antagonist; interleukin 1 inhibitor, urine; interleukin 1 receptor antagonist protein; lower sensory nucleus of trigeminal nerve; mandibular; mesoglia; microglial cell; microgliocyte; model organism; nerve cement; neural circuit; neural circuitry; neural plasticity; neuronal; neuropathic pain; neuroplasticity; novel; novel therapeutic intervention; orofacial; painful neuropathy; perivascular glial cell; programs; protein blotting; receptor; research study; resection; response; social role; temporomandibular pain; trigeminal; tumor necrosis factor (unspecified); unspecified interleukin; urine-derived IL1 inhibitor; voltage
Project start date: 1996-09-15
Project end date: 2012-06-30
Budget start date: 22-SEP-2009
Budget end date: 31-AUG-2010
3R01DE011964-12S1 (2009): $51889
2R01DE011964-10A2 (2007): $363750
GONADAL STEROID HORMONAL REGULATION OF PESISTENT PAIN
Ke Ren, Associate Professor
Oral Surgeryuniversity Of Maryland Baltimore
660 W Redwood St, Rm 021
baltimore, Md 21201
Grant 5R01DE012757-03 from National Institute Of Dental & Craniofacial Research IRG: ZDE1
Abstract: Chronic or persistent pain affects millions of adults each year with costs in lost work days, medical treatment and the reduction in the quality of life in the range of billions of dollars. Many of these conditions are gender-related. Women exhibit a higher prevalence of temporomandibular disorders, neuropathic pain, fibromyalgia, migraine headaches and some forms of arthritis. Furthermore, variations in hormonal levels associated with menstrual cycle, menopause, pregnancy and lactation influence pain levels. The purpose of this study is to evaluate the effects of progesterone and progesterone in combination with estrogen on the hyperalgesia and neuronal hyperexcitability associated with a rat model of persistent pain and inflammation. Our major hypothesis is that endogenous reproductive hormones can suppress persistent pain by their influence on a cascade of molecular, biochemical and physiological events at the spinal level involving inhibitory and excitatory amino acids and their receptors, and opioid peptides and their receptors. We will investigate the effects of these hormones on behavioral hyperalgesia, spinal cord neurons, modulation of GABA receptors, expression of opioid receptors and opioid peptides, and NMDA receptor function. Specific Aim 1 will characterize the changes in behavioral inflammatory hyperalgesia produced by progesterone, in lactating females, ovariectomized females with hormone replacement, and castrated males. Specific Aim 2 will determine the effects of progesterone on the development and maintenance of behavioral hyperalgesia, as well as the possible target sites of the antihyperalgesic effects in peripheral tissue, the spinal cord and the brain. Specific Aim 3 will determine that progesterone´s antihyperalgesic effects are mediated, in part, via modulation of GABAA receptor activation. Specific Aim 4 will test the hypothesis that progesterone´s antihyperalgesic effects are opioid-mediated, in part, at the level of the spinal cord. Specific Aim 5 will examine progesterone effects on NMDA receptor function and changes in NMDA receptor subunit gene expression following inflammation and hyperalgesia. In summary, we propose to elucidate the influence of reproductive hormones on mechanisms of persistent pain in a rat model that mimics human chronic pain conditions known to exhibit cyclical or pregnancy-related variations. The findings will be important for the development of new approaches to the management of these conditions
Keywords: analgesia, chronic pain, estrogen, hormone regulation /control mechanism, hyperalgesia, progesterone GABA receptor, NMDA receptor, castration, inflammation, lactation, opioid, opioid receptor, receptor expression, spinal cord laboratory rat
Project start date: 1999-09-01
Project end date: 2003-08-31
5R01DE012757-03 (2001): $198932
5R01DE012757-02 (2000): $197002
1R01DE012757-01 (1999): $198823
GLIAL-CYTOKINE-NEURONAL INTERACTIONS IN THE MECHANISMS OF PERSISTENT PAIN
Ke Ren, Professor
University Of Maryland Baltimore, 620 W Lexington St, 4th Fl, Baltimore, Md 21201-1508
Grant 5R01NS060735-03 from National Institute Of Neurological Disorders And Stroke
Keywords: Abscission; Address; Affect; Agonist; Ammon Horn; Apoplexy; Awareness; Awarenesses; Bears; Behavior; Behavioral; Blotting, Western; Body Tissues; Brain Stem; Brainstem; CNS plasticity; Cachectin; Cachectin-Tumor Necrosis Factor; Causality; Cell Communication and Signaling; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cells; Central Nervous System; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Chemicals; Chronic; Common Rat Strains; Cornu Ammonis; Cytokine Signal Transduction; Cytokine Signaling; Development; Disease; Disorder; Etiology; Event; Excision; Excitatory Amino Acids; Exhibits; Extirpation; Freund`s Adjuvant; Freund`s Complete Adjuvant; Glia; Glial Cells; Glutamate Receptor; Goals; Hippocampus; Hippocampus (Brain); Hortega cell; Hyperalgesia; Hyperalgesic Sensations; IHC; IL-1; IL1; INFLM; Idiopathic Parkinson Disease; Immune; Immune Precipitation; Immunohistochemistry; Immunohistochemistry Staining Method; Immunoprecipitation; Immunostimulants, adjuvants, Freund`s; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injections; Injury; Interleukin I; Interleukin-1; Interleukins; Intracellular Communication and Signaling; Kolliker`s reticulum; Lead; Learning; Lewy Body Parkinson Disease; Link; Literature; Local anesthesia; Long-Term Depression (Neurophysiology); Long-Term Depression (Physiology); Long-Term Potentiation; Long-Term Synaptic Depression; Lymphocyte-Stimulating Hormone; MS (Multiple Sclerosis); Macrophage Cell Factor; Magnesium; Maintenance; Maintenances; Mammals, Rats; Mediator; Mediator of Activation; Mediator of activation protein; Memory; Mg element; Microglia; Modeling; Molecular; Multiple Sclerosis; Musculoskeletal Pain Disorder; N-Methyl-D-Aspartate Receptors; NK-1 Receptors; NK1R; NKIR; NMDA Receptor-Ionophore Complex; NMDA Receptors; NRVS-SYS; Nerve; Nerve Cells; Nerve Transmitter Substances; Nerve Unit; Nervous; Nervous System; Nervous System, CNS; Nervous system structure; Neural Cell; Neuraxis; Neurocyte; Neuroglia; Neuroglial Cells; Neurologic Body System; Neurologic Organ System; Neuronal Plasticity; Neurons; Neuropharmacology; Neurotransmitters; Non-neuronal cell; Outcome Study; Pain; Pain Control; Pain Therapy; Pain management; Painful; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Pb element; Peripheral; Persistent pain; Phosphorylation; Play; Post-Translational Regulation; Posttranslational Regulation; Preparation; Primary Parkinsonism; Process; Protein Phosphorylation; Rat; Rattus; Receptor Activation; Receptor Protein; Receptors, N-Methylaspartate; Receptors, Neurokinin-1; Removal; Research Design; Rheumatic Diseases; Rheumatism; Role; SP-P Receptors; Sclerosis, Disseminated; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signal Transduction Systems; Signaling; Site; Slice; Source; Staging; Stimulus; Stroke; Structure; Study Type; Study models; Study, Outcome; Substance P Receptor; Surgical Removal; Synapses; Synaptic; T Helper Factor; TAC1R; TACR1; TNF (unspecified); TNF Receptor Ligands; TNF-alpha; Tachykinin Receptor 1; Testing; Time; Tissue Model; Tissues; Tumor Necrosis Factor; Tumor Necrosis Factor Family Protein; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ursidae; Ursidae Family; V (voltage); Vascular Accident, Brain; Western Blotting; Western Blottings; Western Immunoblotting; Work; Yang; active control; biological signal transduction; brain attack; central sensitization; cerebral vascular accident; chemical release; chronic pain; chronic painful condition; cytokine; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; excitatory aminoacid; experiment; experimental research; experimental study; functional mimics; gitter cell; heavy metal Pb; heavy metal lead; hippocampal; hyperalgia; inflammatory pain; inhibitor; inhibitor/antagonist; injury response; insular sclerosis; long term depression; lymphocyte activating factor; mesoglia; microglial cell; microgliocyte; nerve cement; neural circuit; neural circuitry; neural plasticity; neuronal; neuropathic pain; neuroplasticity; novel; painful neuropathy; perivascular glial cell; protein blotting; receptor; research study; resection; response to injury; social role; stroke; study design; tumor necrosis factor (unspecified); unspecified interleukin; voltage
Project start date: 2008-05-01
Project end date: 2013-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-07-088
5R01NS060735-03 (2010): $324845
Sponsored Links Excellgen http://Excellgen.com
Mechanisms Of Persistent Temporomandibular Pain
Ke Ren, Associate Professor
Oral & Craniofacial Biol Scisuniversity Of Maryland Baltimore
660 W Redwood St, Rm 021
baltimore, Md 21201
Grant 2R01DE011964-05A1 from National Institute Of Dental & Craniofacial Research IRG: ZRG1
Project start date: 1996-09-15
Project end date: 2006-06-30
2R01DE011964-05A1 (2001): $298617
1R01DE011964-01 (1996): $219621
3R01DE011964-01S1 (1996): $6200