Paul Durham - Academia.edu (original) (raw)
Papers by Paul Durham
Journal of orofacial pain, 2012
AIMS To test the reliability and validity of a novel rat-holding device designed to be used in co... more AIMS To test the reliability and validity of a novel rat-holding device designed to be used in conjunction with the plantar test apparatus for studying nocifensive behavioral responses in an established model of temporomandibular joint (TMJ) pathology. METHODS Thirty-five young adult male Sprague-Dawley rats were used. Withdrawal latencies in response to infrared 40 heat stimulation of the submandibular region in naïve animals (n = 4) and animals injected with saline or complete Freund's adjuvant (CFA) in the TMJ (n > 9) were measured over a 2-week time period. Nocifensive responses to mechanical stimulation of the cutaneous tissue directly over the TMJ with von Frey filaments were investigated in animals injected with CFA in the TMJ (n = 6). The effect on nocifensive responses to heat and mechanical stimulation of subcutaneous administration of buprenorphine (0.05 mg/kg) into the hindquarter was assessed in CFA and cotreated animals (n = 6). Statistical analysis was performe...
ObjectiveThe focus of this study was to characterize shifts in the rodent gut microbiota that occ... more ObjectiveThe focus of this study was to characterize shifts in the rodent gut microbiota that occur as a result from the oral administration of the commercial chicken broth formulation AAC1. Backgr...
Concerns of emergent widespread silver resistance in clinical bacteria have been raised due to th... more Concerns of emergent widespread silver resistance in clinical bacteria have been raised due to the increased utilization of inorganic silver in wound dressings. Although the molecular basis for silver-resistance has been previously characterized, to date, phenotypic expression of these genes has not been observed in clinical settings. Here we identified the first strains of clinical bacteria expressing silver-resistance at a level that could significantly impact wound care and the use of silver-dressings. After IRB approval, preliminary screening of 859 isolates identified 67 samples potentially harboring silver-resistant genes. Colony PCR confirmed 31 isolates had at least 1 silver-resistant gene. Next, we investigated whether the bacteria possessing silver-resistant genes expressed this trait phenotypically. Despite carrying silver-resistant genes, minimal inhibitory concentration (MIC) testing revealed that most of the bacteria displayed little or no increase in resistance to ion...
PAIN Reports
Noninvasive vagus nerve stimulation suppressed persistent trigeminal nociception in a chronic hea... more Noninvasive vagus nerve stimulation suppressed persistent trigeminal nociception in a chronic headache model similarly to morphine and may provide a safe, nonaddictive abortive therapy for chronic headache.
Brain Research
The pathology of migraine, a common neurological disease, involves sensitization and activation o... more The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naïve offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine.
PAIN Reports
Introduction: Although neck muscle tension is considered a risk factor for migraine, pungent odor... more Introduction: Although neck muscle tension is considered a risk factor for migraine, pungent odors can act as a trigger to initiate an attack in sensitized individuals. Although noninvasive vagus nerve stimulation (nVNS) is now an approved treatment for chronic migraine, how it functions to inhibit trigeminal nociception in an episodic migraine model is not known. Objectives: The objectives of this study were to determine if nVNS could inhibit trigeminal nociception in a novel model of episodic migraine and investigate changes in the expression of proteins implicated in peripheral and central sensitization. Methods: Sprague-Dawley male rats were injected with an inflammatory agent in the trapezius muscle before exposure to pungent volatile compounds, which was used to initiate trigeminal nociceptor activation. The vagus nerve was stimulated transdermally by a 1-ms pulse of 5 kHz sine waves, repeated at 25 Hz for 2 minutes. Nocifensive head withdrawal response to von Frey filaments was determined and immunoreactive protein levels in the spinal cord and trigeminal ganglion (TG) were investigated. Results: Exposure to the pungent odor significantly increased the number of nocifensive withdrawals in response to mechanical stimulation of sensitized TG neurons mediated by neck muscle inflammation. Noninvasive vagus nerve stimulation inhibited nociception and repressed elevated levels of PERK in TG, Iba1 in microglia, and GFAP in astrocytes from sensitized animals exposed to the pungent odor. Conclusion: Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine.
Current Pain and Headache Reports
The neuropeptide calcitonin gene-related peptide (CGRP) is implicated in the underlying pathology... more The neuropeptide calcitonin gene-related peptide (CGRP) is implicated in the underlying pathology of migraine by promoting the development of a sensitized state of primary and secondary nociceptive neurons. The ability of CGRP to initiate and maintain peripheral and central sensitization is mediated by modulation of neuronal, glial, and immune cells in the trigeminal nociceptive signaling pathway. There is accumulating evidence to support a key role of CGRP in promoting cross excitation within the trigeminal ganglion that may help to explain the high co-morbidity of migraine with rhinosinusitis and temporomandibular joint disorder. In addition, there is emerging evidence that CGRP facilitates and sustains a hyperresponsive neuronal state in migraineurs mediated by reported risk factors such as stress and anxiety. In this review, the significant role of CGRP as a modulator of the trigeminal system will be discussed to provide a better understanding of the underlying pathology associated with the migraine phenotype.
Allergy, 2011
Intranasal noninhaled delivery of carbon dioxide (CO₂) is efficacious in the symptomatic treatmen... more Intranasal noninhaled delivery of carbon dioxide (CO₂) is efficacious in the symptomatic treatment of seasonal allergic rhinitis. The goal of this study was to determine whether and how 100% CO₂ inhibits mast cell degranulation, thereby possibly contributing to the reduction of symptoms in seasonal allergic rhinitis. Peritoneal mast cells isolated from rats and labelled with sulforhodamine-B (SFRM-B) were used to determine whether CO₂ treatment could block mast cell degranulation and histamine release in response to 48/80. In addition, the effect of CO₂ on intracellular calcium levels in unstimulated and stimulated mast cells was determined by fluorescent microscopy. Treatment with 48/80 caused >90% of mast cells containing SFRM-B to degranulate, resulting in a marked decrease in the fluorescent intensity within the mast cells, and simultaneously causing a significant increase in histamine release. Significantly, the stimulatory effect of 48/80 on fluorescent intensity and histamine levels was greatly inhibited (>95%) to near control levels by pretreatment with 100% CO₂. Treatment with 48/80 also caused a robust transient increase in intracellular calcium, whereas pretreatment with CO₂ repressed the increase in calcium (>70%) in response to 48/80. Results from this study provide the first evidence of a unique regulatory mechanism by which CO₂ inhibits mast cell degranulation and histamine release by repressing stimulated increases in intracellular calcium. Thus, our data provide a plausible explanation for the reported therapeutic benefit of noninhaled intranasal delivery of 100% CO₂ to treat allergic rhinitis.
Journal of Inorganic Biochemistry
Journal of Oral & Facial Pain and Headache
Aims: To test a commercially available enriched chicken bone broth (ECBB) product for its potenti... more Aims: To test a commercially available enriched chicken bone broth (ECBB) product for its potential anti-inflammatory properties and to evaluate its ability to reduce nociception and expression of protein kinase A (PKA) in a clinically relevant model of temporomandibular disorder (TMD) caused by prolonged jaw opening in rats. Methods: The potential of the ECBB and of a homemade broth was investigated using the Folin-Ciocalteu reagent and percent inhibition of cyclooxygenase-2 (COX-2) activity, which was determined using a commercially available kit. Additionally, the effect of ECBB and homemade broth on nocifensive head withdrawal responses to mechanical stimulation in male Sprague-Dawley rats subjected to prolonged jaw opening was evaluated. Differences were considered significant at P < .025. Changes in PKA expression in the medullary dorsal horn region of the spinal trigeminal nucleus associated with prolonged jaw opening were assessed using immunofluorescence, and these changes were considered significant at P < .05. Behavioral data were analyzed by using multiple nonparametric tests, and immunohistochemistry data were analyzed by using oneway analysis of variance with Games-Howell post hoc tests in SPSS software. Results: ECBB exhibited greater reducing potential and inhibition of COX-2 activity compared to homemade broth. Near maximal jaw opening was sufficient to induce sustained nocifensive responses to mechanical stimuli for 7 days. This increased sensitivity was correlated with elevated levels of the active form of PKA. Importantly, dietary inclusion of ECBB, but not of homemade broth, for 2 weeks prior to jaw opening was sufficient to reduce nocifensive behaviors and PKA expression. Conclusion: Findings from this study provide evidence that ECBB attenuates nociception and expression of the pro-inflammatory protein PKA and thus may be beneficial as a nutraceutical supplement to manage inflammatory pain associated with TMD.
Frontiers in Neurology
Migraine is a prevalent neurological disease that is characterized by unpredictable episodic atta... more Migraine is a prevalent neurological disease that is characterized by unpredictable episodic attacks of intense head pain. The underlying pathology involves sensitization and activation of the trigeminal system. Although non-invasive vagus nerve stimulation (nVNS) is recommended for the treatment of migraine, the abortive mechanism of action is not well-understood. The goal of this study was to compare the ability of nVNS and sumatriptan to inhibit trigeminal activation in two animal models of episodic migraine and to investigate the receptor mechanism of action of nVNS. Nocifensive head withdrawal response was investigated in adult male Sprague Dawley rats using von Frey filaments. To induce trigeminal nociceptor sensitization, complete Freund's adjuvant was injected in the trapezius muscle and trigeminal neurons were activated by exposure to a pungent odor or injection of the nitric oxide donor sodium nitroprusside. Some animals received nVNS or sumatriptan as treatment. Some animals were injected intracisternally with antagonists of GABA A , 5-HT3 or 5-HT7 receptors prior to nVNS since these receptors are implicated in descending modulation. While unsensitized animals exposed to the pungent odor or nitric oxide alone did not exhibit enhanced mechanical nociception, sensitized animals with neck muscle inflammation displayed increased trigeminal nocifensive responses. The enhanced nociceptive response to both stimuli was attenuated by nVNS and sumatriptan. Administration of antagonists of GABA A , 5-HT3, and 5-HT7 receptors in the upper spinal cord suppressed the anti-nocifensive effect of nVNS. Our findings suggest that nVNS inhibits trigeminal activation to a similar degree as sumatriptan in episodic migraine models via involvement of GABAergic and serotonergic signaling to enhance central descending pain modulation.
The Scientific World JOURNAL
The neuropeptide calcitonin gene-related peptide (CGRP) is a potent regulator of cerebral vascula... more The neuropeptide calcitonin gene-related peptide (CGRP) is a potent regulator of cerebral vascular tone and contributes to neurogenic inflammation. Clinical studies have shown that CGRP levels are elevated during the painful phase of migraine headache, then restored to baseline by antimigraine 5-HT1 drugs. Conversely, CGRP is depleted in perivascular nerve terminals from patients who have suffered vasospasm following subarachnoid hemorrhage. We have investigated the mechanisms controlling CGRP expression in the trigeminal ganglia neurons, which provide virtually all of the CGRP innervation to the cerebral vasculature. We found that nerve depolarization, inflammatory compounds, and nitric oxide can increase CGRP synthesis and secretion. Using both adenoviral vectors and transfection approaches, we have shown that the increased synthesis is due to activation of a cell-specific MAP kinase-responsive enhancer upstream of the CGRP gene. Interestingly, the 5-HT1 migraine drugs are able to...
Zeitschrift für Naturforschung C
To establish the substrate specificity of the thioglucoside glucohydrolase myrosinase (EC 3.2.3.1... more To establish the substrate specificity of the thioglucoside glucohydrolase myrosinase (EC 3.2.3.1), this enzyme was purified to homogeneity from light-grown cress (Lepidium sativum L.) seedlings by Sephadex gel filtration. Red Dye and anion exchange (FPLC Mono Q) chromatography, and preparative isoelectric focusing. Hydrolytic activity was shown toward only 4 of the 29 synthetic and natural O-and S-glycosides tested. Highest activity was displayed with the endogenous glucosinolates benzylglucosinolate (Km, 295 μM) and sinigrin (Km, 300 μM) at an optimum pH of 5.5 in sodium citrate buffer. The synthetic glycosides PNPG (Km, 2.0 mM) and ONPG were poorer substrates at an optimum pH of 6.5 in potassium phosphate buffer. The enzyme was inactive with all other nitrophenyl glycosides tested including PNP-a-D-glucoside and PNP-thio-β-D-glucoside, suggesting a requirement for O-β-D-glucose as the glycone moiety within these substrates. PNPG hydrolysis was stimulated 2.6-fold by ascorbate (...
Journal of Oral & Facial Pain and Headache
Aims: To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal gangl... more Aims: To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal ganglion (TG) associated with trigeminal nociception mediated by inflammation in the temporomandibular joint (TMJ). Methods: Male Sprague-Dawley rats (n = 86) were utilized to investigate cellular and behavioral responses to prolonged TMJ inflammation caused by bilateral injection of Complete Freund's Adjuvant (CFA) in the TMJ capsules. To investigate the cellular effects of protein kinase A (PKA) in the STN, rats were injected intrathecally with the selective PKA inhibitor KT5720 prior to injection of CFA into both TMJ capsules. Levels of calcitonin gene-related peptide (CGRP), active PKA, and ionized calciumbinding adapter molecule 1 (Iba1) in the STN and expression of phosphorylated extracellular regulated kinases (p-ERK) in the TG were determined with immunohistochemistry (n ≥ 3 experiments per test condition). Nocifensive head withdrawal responses to mechanical stimulation of the cutaneous tissue over the TMJ were monitored following CFA injection in the absence or presence of KT5720 (n = 7). Statistical analysis was performed using parametric analysis of variance (ANOVA) tests. Results: Intrathecal injection of KT5720 significantly inhibited the stimulatory effect of CFA on levels of CGRP, PKA, and Iba1 in the STN. In addition, administration of KT5720 decreased the average number of CFA-induced nocifensive withdrawal responses to mechanical stimulation and the CFA-mediated increase in pERK expression in the ganglion. Conclusion: These findings provide evidence that elevated PKA activity in the STN promotes cellular events temporally associated with trigeminal nociception caused by prolonged TMJ inflammation.
Otolaryngology-Head and Neck Surgery
Journal of Speech Language and Hearing Research, Sep 1, 1987
The twitch response of the canine vocalis muscle was investigated through a series of experiments... more The twitch response of the canine vocalis muscle was investigated through a series of experiments conducted in vitro. Samples of vocalis muscle were dissected and prepared from canine larynges a few minutes before death and kept in Krebs solution at a temperature of 37 +/- 1 degrees C and pH of 7.4 +/- 0.05. Field stimulation with parallel-plate silver electrodes was applied to study the twitch response of muscle samples. The peak tension and time course of isometric contraction of isolated muscle samples were measured electronically with a Cambridge Technology Dual Servo System (ergometer). Contraction time and 50% relaxation time of this muscle were measured for seven samples at various levels of strain. It was found that contraction time ranged between 22 and 32 ms and 50% relaxation time ranged between 17 and 37 ms. Results indicate that the vocalis muscle is a fast muscle capable of performing rapid maneuvers in support of changes in fundamental frequency.
Journal of orofacial pain, 2012
AIMS To test the reliability and validity of a novel rat-holding device designed to be used in co... more AIMS To test the reliability and validity of a novel rat-holding device designed to be used in conjunction with the plantar test apparatus for studying nocifensive behavioral responses in an established model of temporomandibular joint (TMJ) pathology. METHODS Thirty-five young adult male Sprague-Dawley rats were used. Withdrawal latencies in response to infrared 40 heat stimulation of the submandibular region in naïve animals (n = 4) and animals injected with saline or complete Freund's adjuvant (CFA) in the TMJ (n > 9) were measured over a 2-week time period. Nocifensive responses to mechanical stimulation of the cutaneous tissue directly over the TMJ with von Frey filaments were investigated in animals injected with CFA in the TMJ (n = 6). The effect on nocifensive responses to heat and mechanical stimulation of subcutaneous administration of buprenorphine (0.05 mg/kg) into the hindquarter was assessed in CFA and cotreated animals (n = 6). Statistical analysis was performe...
ObjectiveThe focus of this study was to characterize shifts in the rodent gut microbiota that occ... more ObjectiveThe focus of this study was to characterize shifts in the rodent gut microbiota that occur as a result from the oral administration of the commercial chicken broth formulation AAC1. Backgr...
Concerns of emergent widespread silver resistance in clinical bacteria have been raised due to th... more Concerns of emergent widespread silver resistance in clinical bacteria have been raised due to the increased utilization of inorganic silver in wound dressings. Although the molecular basis for silver-resistance has been previously characterized, to date, phenotypic expression of these genes has not been observed in clinical settings. Here we identified the first strains of clinical bacteria expressing silver-resistance at a level that could significantly impact wound care and the use of silver-dressings. After IRB approval, preliminary screening of 859 isolates identified 67 samples potentially harboring silver-resistant genes. Colony PCR confirmed 31 isolates had at least 1 silver-resistant gene. Next, we investigated whether the bacteria possessing silver-resistant genes expressed this trait phenotypically. Despite carrying silver-resistant genes, minimal inhibitory concentration (MIC) testing revealed that most of the bacteria displayed little or no increase in resistance to ion...
PAIN Reports
Noninvasive vagus nerve stimulation suppressed persistent trigeminal nociception in a chronic hea... more Noninvasive vagus nerve stimulation suppressed persistent trigeminal nociception in a chronic headache model similarly to morphine and may provide a safe, nonaddictive abortive therapy for chronic headache.
Brain Research
The pathology of migraine, a common neurological disease, involves sensitization and activation o... more The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naïve offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine.
PAIN Reports
Introduction: Although neck muscle tension is considered a risk factor for migraine, pungent odor... more Introduction: Although neck muscle tension is considered a risk factor for migraine, pungent odors can act as a trigger to initiate an attack in sensitized individuals. Although noninvasive vagus nerve stimulation (nVNS) is now an approved treatment for chronic migraine, how it functions to inhibit trigeminal nociception in an episodic migraine model is not known. Objectives: The objectives of this study were to determine if nVNS could inhibit trigeminal nociception in a novel model of episodic migraine and investigate changes in the expression of proteins implicated in peripheral and central sensitization. Methods: Sprague-Dawley male rats were injected with an inflammatory agent in the trapezius muscle before exposure to pungent volatile compounds, which was used to initiate trigeminal nociceptor activation. The vagus nerve was stimulated transdermally by a 1-ms pulse of 5 kHz sine waves, repeated at 25 Hz for 2 minutes. Nocifensive head withdrawal response to von Frey filaments was determined and immunoreactive protein levels in the spinal cord and trigeminal ganglion (TG) were investigated. Results: Exposure to the pungent odor significantly increased the number of nocifensive withdrawals in response to mechanical stimulation of sensitized TG neurons mediated by neck muscle inflammation. Noninvasive vagus nerve stimulation inhibited nociception and repressed elevated levels of PERK in TG, Iba1 in microglia, and GFAP in astrocytes from sensitized animals exposed to the pungent odor. Conclusion: Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine.
Current Pain and Headache Reports
The neuropeptide calcitonin gene-related peptide (CGRP) is implicated in the underlying pathology... more The neuropeptide calcitonin gene-related peptide (CGRP) is implicated in the underlying pathology of migraine by promoting the development of a sensitized state of primary and secondary nociceptive neurons. The ability of CGRP to initiate and maintain peripheral and central sensitization is mediated by modulation of neuronal, glial, and immune cells in the trigeminal nociceptive signaling pathway. There is accumulating evidence to support a key role of CGRP in promoting cross excitation within the trigeminal ganglion that may help to explain the high co-morbidity of migraine with rhinosinusitis and temporomandibular joint disorder. In addition, there is emerging evidence that CGRP facilitates and sustains a hyperresponsive neuronal state in migraineurs mediated by reported risk factors such as stress and anxiety. In this review, the significant role of CGRP as a modulator of the trigeminal system will be discussed to provide a better understanding of the underlying pathology associated with the migraine phenotype.
Allergy, 2011
Intranasal noninhaled delivery of carbon dioxide (CO₂) is efficacious in the symptomatic treatmen... more Intranasal noninhaled delivery of carbon dioxide (CO₂) is efficacious in the symptomatic treatment of seasonal allergic rhinitis. The goal of this study was to determine whether and how 100% CO₂ inhibits mast cell degranulation, thereby possibly contributing to the reduction of symptoms in seasonal allergic rhinitis. Peritoneal mast cells isolated from rats and labelled with sulforhodamine-B (SFRM-B) were used to determine whether CO₂ treatment could block mast cell degranulation and histamine release in response to 48/80. In addition, the effect of CO₂ on intracellular calcium levels in unstimulated and stimulated mast cells was determined by fluorescent microscopy. Treatment with 48/80 caused >90% of mast cells containing SFRM-B to degranulate, resulting in a marked decrease in the fluorescent intensity within the mast cells, and simultaneously causing a significant increase in histamine release. Significantly, the stimulatory effect of 48/80 on fluorescent intensity and histamine levels was greatly inhibited (>95%) to near control levels by pretreatment with 100% CO₂. Treatment with 48/80 also caused a robust transient increase in intracellular calcium, whereas pretreatment with CO₂ repressed the increase in calcium (>70%) in response to 48/80. Results from this study provide the first evidence of a unique regulatory mechanism by which CO₂ inhibits mast cell degranulation and histamine release by repressing stimulated increases in intracellular calcium. Thus, our data provide a plausible explanation for the reported therapeutic benefit of noninhaled intranasal delivery of 100% CO₂ to treat allergic rhinitis.
Journal of Inorganic Biochemistry
Journal of Oral & Facial Pain and Headache
Aims: To test a commercially available enriched chicken bone broth (ECBB) product for its potenti... more Aims: To test a commercially available enriched chicken bone broth (ECBB) product for its potential anti-inflammatory properties and to evaluate its ability to reduce nociception and expression of protein kinase A (PKA) in a clinically relevant model of temporomandibular disorder (TMD) caused by prolonged jaw opening in rats. Methods: The potential of the ECBB and of a homemade broth was investigated using the Folin-Ciocalteu reagent and percent inhibition of cyclooxygenase-2 (COX-2) activity, which was determined using a commercially available kit. Additionally, the effect of ECBB and homemade broth on nocifensive head withdrawal responses to mechanical stimulation in male Sprague-Dawley rats subjected to prolonged jaw opening was evaluated. Differences were considered significant at P < .025. Changes in PKA expression in the medullary dorsal horn region of the spinal trigeminal nucleus associated with prolonged jaw opening were assessed using immunofluorescence, and these changes were considered significant at P < .05. Behavioral data were analyzed by using multiple nonparametric tests, and immunohistochemistry data were analyzed by using oneway analysis of variance with Games-Howell post hoc tests in SPSS software. Results: ECBB exhibited greater reducing potential and inhibition of COX-2 activity compared to homemade broth. Near maximal jaw opening was sufficient to induce sustained nocifensive responses to mechanical stimuli for 7 days. This increased sensitivity was correlated with elevated levels of the active form of PKA. Importantly, dietary inclusion of ECBB, but not of homemade broth, for 2 weeks prior to jaw opening was sufficient to reduce nocifensive behaviors and PKA expression. Conclusion: Findings from this study provide evidence that ECBB attenuates nociception and expression of the pro-inflammatory protein PKA and thus may be beneficial as a nutraceutical supplement to manage inflammatory pain associated with TMD.
Frontiers in Neurology
Migraine is a prevalent neurological disease that is characterized by unpredictable episodic atta... more Migraine is a prevalent neurological disease that is characterized by unpredictable episodic attacks of intense head pain. The underlying pathology involves sensitization and activation of the trigeminal system. Although non-invasive vagus nerve stimulation (nVNS) is recommended for the treatment of migraine, the abortive mechanism of action is not well-understood. The goal of this study was to compare the ability of nVNS and sumatriptan to inhibit trigeminal activation in two animal models of episodic migraine and to investigate the receptor mechanism of action of nVNS. Nocifensive head withdrawal response was investigated in adult male Sprague Dawley rats using von Frey filaments. To induce trigeminal nociceptor sensitization, complete Freund's adjuvant was injected in the trapezius muscle and trigeminal neurons were activated by exposure to a pungent odor or injection of the nitric oxide donor sodium nitroprusside. Some animals received nVNS or sumatriptan as treatment. Some animals were injected intracisternally with antagonists of GABA A , 5-HT3 or 5-HT7 receptors prior to nVNS since these receptors are implicated in descending modulation. While unsensitized animals exposed to the pungent odor or nitric oxide alone did not exhibit enhanced mechanical nociception, sensitized animals with neck muscle inflammation displayed increased trigeminal nocifensive responses. The enhanced nociceptive response to both stimuli was attenuated by nVNS and sumatriptan. Administration of antagonists of GABA A , 5-HT3, and 5-HT7 receptors in the upper spinal cord suppressed the anti-nocifensive effect of nVNS. Our findings suggest that nVNS inhibits trigeminal activation to a similar degree as sumatriptan in episodic migraine models via involvement of GABAergic and serotonergic signaling to enhance central descending pain modulation.
The Scientific World JOURNAL
The neuropeptide calcitonin gene-related peptide (CGRP) is a potent regulator of cerebral vascula... more The neuropeptide calcitonin gene-related peptide (CGRP) is a potent regulator of cerebral vascular tone and contributes to neurogenic inflammation. Clinical studies have shown that CGRP levels are elevated during the painful phase of migraine headache, then restored to baseline by antimigraine 5-HT1 drugs. Conversely, CGRP is depleted in perivascular nerve terminals from patients who have suffered vasospasm following subarachnoid hemorrhage. We have investigated the mechanisms controlling CGRP expression in the trigeminal ganglia neurons, which provide virtually all of the CGRP innervation to the cerebral vasculature. We found that nerve depolarization, inflammatory compounds, and nitric oxide can increase CGRP synthesis and secretion. Using both adenoviral vectors and transfection approaches, we have shown that the increased synthesis is due to activation of a cell-specific MAP kinase-responsive enhancer upstream of the CGRP gene. Interestingly, the 5-HT1 migraine drugs are able to...
Zeitschrift für Naturforschung C
To establish the substrate specificity of the thioglucoside glucohydrolase myrosinase (EC 3.2.3.1... more To establish the substrate specificity of the thioglucoside glucohydrolase myrosinase (EC 3.2.3.1), this enzyme was purified to homogeneity from light-grown cress (Lepidium sativum L.) seedlings by Sephadex gel filtration. Red Dye and anion exchange (FPLC Mono Q) chromatography, and preparative isoelectric focusing. Hydrolytic activity was shown toward only 4 of the 29 synthetic and natural O-and S-glycosides tested. Highest activity was displayed with the endogenous glucosinolates benzylglucosinolate (Km, 295 μM) and sinigrin (Km, 300 μM) at an optimum pH of 5.5 in sodium citrate buffer. The synthetic glycosides PNPG (Km, 2.0 mM) and ONPG were poorer substrates at an optimum pH of 6.5 in potassium phosphate buffer. The enzyme was inactive with all other nitrophenyl glycosides tested including PNP-a-D-glucoside and PNP-thio-β-D-glucoside, suggesting a requirement for O-β-D-glucose as the glycone moiety within these substrates. PNPG hydrolysis was stimulated 2.6-fold by ascorbate (...
Journal of Oral & Facial Pain and Headache
Aims: To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal gangl... more Aims: To investigate cellular changes in the spinal trigeminal nucleus (STN) and trigeminal ganglion (TG) associated with trigeminal nociception mediated by inflammation in the temporomandibular joint (TMJ). Methods: Male Sprague-Dawley rats (n = 86) were utilized to investigate cellular and behavioral responses to prolonged TMJ inflammation caused by bilateral injection of Complete Freund's Adjuvant (CFA) in the TMJ capsules. To investigate the cellular effects of protein kinase A (PKA) in the STN, rats were injected intrathecally with the selective PKA inhibitor KT5720 prior to injection of CFA into both TMJ capsules. Levels of calcitonin gene-related peptide (CGRP), active PKA, and ionized calciumbinding adapter molecule 1 (Iba1) in the STN and expression of phosphorylated extracellular regulated kinases (p-ERK) in the TG were determined with immunohistochemistry (n ≥ 3 experiments per test condition). Nocifensive head withdrawal responses to mechanical stimulation of the cutaneous tissue over the TMJ were monitored following CFA injection in the absence or presence of KT5720 (n = 7). Statistical analysis was performed using parametric analysis of variance (ANOVA) tests. Results: Intrathecal injection of KT5720 significantly inhibited the stimulatory effect of CFA on levels of CGRP, PKA, and Iba1 in the STN. In addition, administration of KT5720 decreased the average number of CFA-induced nocifensive withdrawal responses to mechanical stimulation and the CFA-mediated increase in pERK expression in the ganglion. Conclusion: These findings provide evidence that elevated PKA activity in the STN promotes cellular events temporally associated with trigeminal nociception caused by prolonged TMJ inflammation.
Otolaryngology-Head and Neck Surgery
Journal of Speech Language and Hearing Research, Sep 1, 1987
The twitch response of the canine vocalis muscle was investigated through a series of experiments... more The twitch response of the canine vocalis muscle was investigated through a series of experiments conducted in vitro. Samples of vocalis muscle were dissected and prepared from canine larynges a few minutes before death and kept in Krebs solution at a temperature of 37 +/- 1 degrees C and pH of 7.4 +/- 0.05. Field stimulation with parallel-plate silver electrodes was applied to study the twitch response of muscle samples. The peak tension and time course of isometric contraction of isolated muscle samples were measured electronically with a Cambridge Technology Dual Servo System (ergometer). Contraction time and 50% relaxation time of this muscle were measured for seven samples at various levels of strain. It was found that contraction time ranged between 22 and 32 ms and 50% relaxation time ranged between 17 and 37 ms. Results indicate that the vocalis muscle is a fast muscle capable of performing rapid maneuvers in support of changes in fundamental frequency.