[Show abstract][Hide abstract] ABSTRACT: The rostral ventromedial medulla (RVM) projects to the medullary and spinal dorsal horns and is a major source of descending modulation of nociceptive transmission. Traditionally, neurons in the RVM are classified functionally as ON, OFF and NEUTRAL cells based on responses to noxious cutaneous stimulation of the tail or hind paw. ON cells facilitate nociceptive transmission, OFF cells are inhibitory, whereas NEUTRAL cells are unresponsive to noxious stimuli and their role in pain modulation is unclear. Classification of RVM neurons with respect to stimulation of craniofacial tissues is not well defined. In isoflurane-anesthetized male rats, RVM neurons first were classified as ON (25.5%), OFF (25.5%) or NEUTRAL cells (49%) by noxious tail pinch. Pinching the skin overlying the temporomandibular joint (TMJ) altered the proportions of ON (39.2%) and OFF (42.2%) and NEUTRAL cells (19.6%). To assess the response of RVM cells to specialized craniofacial inputs, adenosine triphosphate (ATP; 0.01-1 mM) was injected into the TMJ (0.01-1 mM ATP) and capsaicin (0.1%) was applied to the ocular surface. TMJ and ocular surface stimulation also resulted in a reduced proportion of NEUTRAL cells compared to tail pinch. Dose-effect analyses revealed that ON and OFF cells encoded the intra-TMJ concentration of ATP. These results suggest that somatotopy plays a significant role in the functional classification of RVM cells and support the notion that NEUTRAL cells likely are sub-groups of ON and OFF cells. It is suggested that a portion of RVM neurons serves different functions in modulating craniofacial and spinal pain conditions.
Journal of Neurophysiology 09/2014; · 3.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cornea-evoked eyeblinks maintain tear film integrity on the ocular surface in response to dryness and protect the eye from real or potential damage. Eyelid movement following electrical stimulation has been well studied in humans and animals; however, the central neural pathways that mediate protective eyeblinks following natural nociceptive signals are less certain. The aim of this study was to assess the role of the trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition and subnucleus caudalis/upper cervical cord (Vc/C1) junction regions on orbicularis oculi electromyographic (OOemg) activity evoked by ocular surface application of hypertonic saline or exposure to bright light in urethane anesthetized male rats. The Vi/Vc and Vc/C1 regions are the main sites of termination for trigeminal afferent nerves that supply the ocular surface, while hypertonic saline (saline = 0.15-5M) and bright light (light = 5-20k lux) selectively activate ocular surface and intraocular trigeminal nerves, respectively, and excite second-order neurons at the Vi/Vc and Vc/C1 regions. Integrated OOemg activity, ipsilateral to the applied stimulus, increased with greater stimulus intensities for both modalities. Lidocaine applied to the ocular surface inhibited OOemg responses to hypertonic saline, but did not alter the response to light. Lidocaine injected into the trigeminal ganglion blocked completely the OOemg responses to hypertonic saline and light indicating a trigeminal afferent origin. Synaptic blockade by cobalt chloride of the Vi/Vc or Vc/C1 region greatly reduced OOemg responses to hypertonic saline and bright light. These data indicate that OOemg activity evoked by natural stimuli known to cause irritation or discomfort in humans depends on a relay in both the Vi/Vc transition and Vc/C1 junction regions.
[Show abstract][Hide abstract] ABSTRACT: Orexin-A (OxA) is synthesized in posterior and lateral regions of the hypothalamus and contributes to homeostatic regulation of body functions including pain modulation. To determine if orexinergic mechanisms contribute to posterior hypothalamus (PH)-induced modulation of ocular input to subnucleus caudalis/upper cervical (Vc/C1) neurons, the orexin-1 receptor antagonist SB334867 was applied to the dorsal brainstem surface prior to PH disinhibition, by bicuculline methiodide, in male rats under isoflurane anesthesia. Ocular input to Vc/C1 units by bright light or hypertonic saline was markedly reduced by PH disinhibition and reversed completely by local Vc/C1 application of SB334867. OxA applied to the Vc/C1 surface mimicked the effects of PH disinhibition in a dose-dependent manner. OxA-induced inhibition was prevented by co-application of SB334867, but not by the orexin-2 receptor antagonist TCS Ox2 29. PH disinhibition and local OxA application also reduced the high threshold convergent cutaneous receptive field area of ocular units, suggesting widespread effects on somatic input to Vc/C1 ocular units. Vc/C1 application of OxA or SB334867 alone did not affect the background discharge of ocular units and suggested that the PH-OxA influence on ocular unit activity was not tonically active. Vc/C1 application of OxA or SB334867 alone also did not alter mean arterial pressure, whereas PH disinhibition evoked prompt and sustained increases. These results suggest that stimulus-evoked increases in PH outflow acts through OxA and orexin-1 receptors to alter the encoding properties of trigeminal brainstem neurons responsive to input from the ocular surface and deep tissues of the eye.
European Journal of Neuroscience 06/2014; · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sensory input from the temporomandibular joint (TMJ) to neurons in superficial laminae at the spinomedullary (Vc/C1-2) region is strongly influenced by estrogen status. This study determined if GABAergic mechanisms play a role in estrogen modulation of TMJ nociceptive processing in ovariectomized female rats treated with high (HE) or low dose (LE) estradiol (E2) for two days. Superficial laminae neurons were activated by ATP (1 mM) injections into the joint space. The selective GABAA receptor antagonist, bicuculline methiodide (BMI, 5 or 50 μM, 30 μl), applied at the site of recording greatly enhanced the magnitude and duration of ATP-evoked responses in LE rats, but not in units from HE rats. The convergent cutaneous receptive field (RF) area of TMJ neurons was enlarged after BMI in LE but not HE rats, while resting discharge rates were increased after BMI independent of estrogen status. By contrast, the selective GABAA receptor agonist, muscimol (50 μM, 30 μl), significantly reduced the magnitude and duration of ATP-evoked activity, resting discharge rate, and cutaneous RF area of TMJ neurons in LE and HE rats, whereas lower doses (5 μM) affected only units from LE rats. Protein levels of GABAA receptor β3 isoform at the Vc/C1-2 region were similar for HE and LE rats. These results suggest that GABAergic mechanisms contribute significantly to background discharge rates and TMJ-evoked input to superficial laminae neurons at the Vc/C1-2 region. Estrogen status may gate the magnitude of GABAergic influence on TMJ neurons at the earliest stages of nociceptive processing at the spinomedullary region.
[Show abstract][Hide abstract] ABSTRACT: Enhanced light sensitivity is a common feature of many neuro-ophthalmic conditions and some chronic headaches. Previously we reported that the bright light-evoked increases in trigeminal brainstem neural activity and lacrimation depended on a neurovascular link within the eye (Okamoto et al., 2012). However, the supraspinal pathways necessary for these light-evoked responses are not well defined. To assess the contribution of the posterior hypothalamic area (PH), a brain region closely associated with control of autonomic outflow, we injected bicuculline methiodide (BMI), a GABAa receptor antagonist, into the PH and determined its effect on the encoding properties of ocular neurons at the ventrolateral trigeminal interpolaris/caudalis transition (Vi/Vc) and caudalis/upper cervical cord junction (Vc/C1) regions and on reflex lacrimation in male rats under isoflurane anesthesia. BMI markedly reduced light-evoked (> 80%) responses of Vi/Vc and Vc/C1 neurons at 10 min with partial recovery by 50 min after injection. BMI also reduced (> 35%) the convergent cutaneous receptive field area of Vi/Vc and Vc/C1 ocular neurons indicating that both intra-ocular and periorbital cutaneous inputs were affected by changes in PH outflow. Light-evoked lacrimation was reduced by > 35% at 10 min after BMI, while resting mean arterial pressure increased promptly and remained elevated (> 20 mmHg) throughout the 50 min post-injection period. These results suggested that PH stimulation, acting in part through increased sympathetic activity, significantly inhibited light- and facial skin-evoked activity of ocular neurons at the Vi/Vc and Vc/C1 region. These data provide further support for the hypothesis that autonomic outflow plays a critical role in mediating light-evoked trigeminal brainstem neural activity and reflex lacrimation.
[Show abstract][Hide abstract] ABSTRACT: Objective:
Low frequency stimulation of peripheral nerves at adequate intensities often results in increased pain sensation and is mediated by central neural processes. Intraoral pain is mediated by trigeminal nerves; however, little is known regarding temporal summation of pain and intraoral stimulus parameters. This study assessed the effects of repeated stimulation of the gingiva on pain sensation in subjects using a device adapted for use in functional imaging environments. Measurement of psychophysical responses provide behavioral context for future investigations of intraoral pain processing using functional imaging methods.
A previously modified fMRI-compatible device was used to deliver punctate pressure-pain stimuli to gingiva apical of the maxillary right premolars. Data was collected from healthy female subjects (n = 24, mean age of 31 year). Mildly painful baseline pressure (1/10 intensity) was determined for each subject prior to temporal summation protocol. The summation protocol consisted of 6 runs of 10 mild pressure-pain stimuli with 3 different inter-stimulus intervals (ISI), which were 2, 5, and 10 seconds in duration, in a randomized block design. Data were analyzed by a two-way repeated measures analysis of variance.
For each ISI, reported pain ratings increased significantly from the first to tenth individual stimuli (p<0.0001). The increase in pain ratings at 2 second ISI was significantly higher than at 5 and 10 second ISIs (p<0.0001 for both). The reported pain increased during individual trials with greater pain intensity ratings occurring with runs that had shorter ISI duration suggests temporal summation occurred (Trial-by-ISI interaction p<0.0001).
Pain ratings increased with stimulation of the gingiva in a frequency-dependent manner, in a similar fashion as observed by others. Experimental paradigm has acceptable properties to proceed with future experiments will rate pain sensation to intraoral stimulation while simultaneous high-resolution fMRI is used to assess brainstem activation.
IADR/AADR/CADR General Session and Exhibition 2013; 03/2013
[Show abstract][Hide abstract] ABSTRACT: Estrogen status and psychological stress contribute to the expression of several chronic pain conditions including temporomandibular muscle and joint disorders (TMJD). Sensory neurons that supply the temporomandibular joint (TMJ) region terminate in laminae I and V of the spinal trigeminal nucleus (Vc/C1-2 region); however, little is known about lamina-specificity and environmental influences on the encoding properties of TMJ brainstem neurons. To test the hypothesis that Vc/C1-2 neurons integrate both interoceptive and exteroceptive signals relevant for TMJ nociception, we recorded TMJ-evoked activity in superficial and deep laminae of ovariectomized rats under high and low estradiol (E2) and stress conditions. Rats received daily injections of low (LE) or high (HE) dose E2 and were subjected to forced swim (FS) or sham swim conditioning for 3days. The results revealed marked lamina-specificity in that HE rats displayed enhanced TMJ-evoked activity in superficial, but not deep, laminae independent of stress conditioning. By contrast, FS conditioned rats displayed increased background firing and TMJ-evoked activity of neurons in deep, but not superficial, laminae independent of E2 status. FS also enhanced TMJ-evoked masseter muscle activity and suggested the importance of deep dorsal horn neurons in mediating evoked jaw muscle activity. In conclusion, E2 status and psychophysical stress play a significant role in modifying the encoding properties of TMJ-responsive medullary dorsal horn neurons with a marked lamina-specificity.
[Show abstract][Hide abstract] ABSTRACT: Abnormal sensitivity to bright light can cause discomfort or pain and evoke protective reflexes such as lacrimation. Although the trigeminal nerve is probably involved, the mechanism linking luminance to somatic sensory nerve activity remains uncertain. This study determined the effect of bright light on second-order ocular neurons at the ventral trigeminal interpolaris/caudalis transition (Vi/Vc) region, a major termination zone for trigeminal sensory fibers that innervate the eye. Most Vi/Vc neurons (80.9%) identified by responses to mechanical stimulation of the ocular surface also encoded bright light intensity. Light-evoked neural activity displayed a long latency to activation (> 10 s) and required transmission through the trigeminal root ganglion. Light-evoked neural activity was inhibited by intravitreal injection of phenylephrine or l-N(G) -nitro-arginine methyl ester (L-NAME), suggesting a mechanism coupled to vascular events within the eye. Laser Doppler flowmetry revealed rapid light-evoked increases in ocular blood flow that occurred prior to the increase in Vi/Vc neural activity. Synaptic blockade of the Vi/Vc region by cobalt chloride prevented light-evoked increases in tear volume, whereas blockade at the more caudal spinomedullary junction (Vc/C1) had no effect. In summary, Vi/Vc neurons encoded bright light intensity and were inhibited by drugs that alter blood flow to the eye. These results support the hypothesis that light-responsive neurons at the Vi/Vc transition region are critical for ocular-specific functions such as reflex lacrimation, whereas neurons at the caudal Vc/C1 junction region probably serve other aspects of ocular nociception.
European Journal of Neuroscience 09/2012; · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Painful temporal summation is thought to be a centrally mediated phenomenon resulting in increased pain intensity produced by repeated stimuli. People with chronic pain conditions have shown increased temporal summation compared to pain-free controls, suggesting altered central nociceptive regulation. Functional 3-Tesla MRI research comparing pain-free controls to Persistent Dento-alveolar Pain disorder patients demonstrated differences in central processing, with large group-wise differences observed within the brainstem. We tested the redeveloped intraoral stimulus device to assess whether temporal summation from gingival pressure-pain stimuli can be obtained.
Method: The MRI-compatible stimulus device was designed to provide dynamic, punctate, gingival pressure ranging from barely perceivable to severely painful. Chair-side device testing established individual thresholds of mild pressure-pain intensity. Temporal summation testing consisted of 6 runs of 10 consecutive, mildly painful stimuli separated by an inter-stimulus interval (ISI) of 2, 5, or 10 seconds for a given run. Perception of pain intensity was continually measured throughout each run. A 3 minute rest period was interposed between runs to reduce the potential for order effects. Data was analyzed by a three-way repeated measures analysis of variance.
Result: Five healthy female subjects were tested (mean age: 32 years). Pain ratings significantly increased with repeated stimuli (P<0.005), and there was a significant trial and ISI interaction (P<0.001). Bonferroni-corrected t-tests showed greater temporal summation at ISI of 2 seconds than 10 seconds (P<0.005), and at 2 second ISI averaged pain intensity ratings for the tenth stimulus were significantly greater than for the first stimulus (P<0.005). Investigation of an order effect revealed no main interaction.
Conclusion: An MRI-compatible intraoral stimulus device capable of producing painful temporal summation was developed. The next step is 7-Tesla MRI testing to produce functional maps of the brainstem to explore central processing of trigeminal-mediated pain.
[Show abstract][Hide abstract] ABSTRACT: Psychological stress is a risk factor for the development of musculoskeletal pain of the head and neck; however, the basis for this relationship remains uncertain. This study tested the hypothesis that psychophysical stress alone was sufficient to alter the encoding properties of spinomedullary dorsal horn neurons and masseter muscle activity in male rats. Repeated forced swim conditioning increased markedly both the background firing rate and temporomandibular joint (TMJ)-evoked activity of neurons in deep dorsal horn, while neurons in superficial laminae were less affected. Stress also increased the responses to stimulation of facial skin overlying the TMJ of neurons in deep and superficial dorsal horn. TMJ-evoked masseter muscle activity was enhanced significantly in stressed rats, an effect that was reduced by prior blockade of the spinomedullary junction region. These data indicated that repeated psychophysical stress induced widespread effects on the properties of medullary dorsal horn neurons and masseter muscle activity. The effects of stress were seen preferentially on neurons in deep dorsal horn and included enhanced responses to chemosensory input from the TMJ and mechanical input from overlying facial skin. The stress-induced elevation in TMJ-evoked masseter muscle activity matched well with the changes seen in dorsal horn neurons. It is concluded that the spinomedullary junction region plays a critical role in the integration of psychophysical stress and sensory information relevant for nociception involving deep craniofacial tissues.
European Journal of Neuroscience 04/2012; 36(1):2025-34. · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several craniofacial pain conditions, including temporomandibular joint disorders (TMJDs), are more prevalent in women than men. The basis for sex differences in deep craniofacial pain is not known. The present study compared the magnitude of ascending projections from temporomandibular joint (TMJ)-responsive neurons in trigeminal brainstem with the ventrolateral periaqueductal gray (vlPAG) or posterior nucleus of the thalamus (Po) in males and female rats. Fluorogold (FG) was injected into vlPAG or Po, and TMJ-responsive neurons were identified by Fos-like immunoreactivity (Fos-LI) after mustard oil injection. TMJ-evoked Fos-LI was similar in males and females; however, significant differences in cell counts were seen for FG single-labeled and Fos/FG double-labeled neurons in trigeminal brainstem. After vlPAG injections, the number of FG-labeled neurons in trigeminal subnucleus interpolaris (Vi), ventral interpolaris/caudalis transition (vl-Vi/Vc), and dorsal paratrigeminal region (dPa5) was greater in females than males. The percentage of Fos/FG double-labeled neurons in vl-Vi/Vc and dPa5 after vlPAG injection also was greater in females than males. In contrast, after Po injections, males displayed a greater number of FG-labeled neurons in superficial laminae (Lam I/II) of trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C(1-2)) and deeper laminae (Lam III/V) at C(1-2) than females. The percentage of Fos/FG double-labeled neurons in Lam I/II of Vc after Po injection also was greater in males than females. These data revealed significant sex differences in ascending projections from TMJ-responsive neurons in trigeminal brainstem. Such differences may influence the ability of males and females to recruit autonomic reflexes and endogenous pain control circuits relevant for TMJ nociception.
[Show abstract][Hide abstract] ABSTRACT: Estrogen status is a risk factor for temporomandibular muscle and joint disorders (TMJD) and other craniofacial pain conditions. The basis for estrogen modulation of pain is poorly understood and has often been attributed to long-term genomic effects. However, estrogens also act rapidly through membrane-initiated mechanisms to alter neural activity. To assess if estrogens act rapidly to affect TMJ-responsive neurons, we applied 17β-estradiol (E2) directly at the spinomedullary (Vc/C(1-2)) region, the initial brainstem site for synaptic integration of TMJ sensory signals, while recording single neuron activity. In ovariectomized female rats, E2 rapidly (within 10 minutes) and reversibly reduced TMJ-evoked neural activity at the Vc/C(1-2) region. The effect was estrogen receptor (ER) subtype-specific, since ERβ agonists inhibited, while an ERβ agonist enhanced, evoked activity. A membrane-mediated mechanism was indicated, since the membrane-impermeable analogue, E(2)-BSA, mimicked the inhibitory effect of E2 and was prevented by an ER antagonist. This study demonstrated that E2 acted rapidly, through membrane-mediated pathways, and locally at the Vc/C(1-2) region, to modulate sensory signals from the TMJ region. These results were consistent with the hypothesis that estrogens can act rapidly at the level of the trigeminal brainstem complex to influence sensory integration of TMJ-related information.
Journal of dental research 11/2011; 91(2):210-4. · 4.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effects of perceptions and behaviors related to culturally patterned socioeconomic obligations on catecholamine excretion rates were studied in a cross-sectional sample of Samoan adults.
A total of 378 participants, ages 29-62 years, from 9 villages throughout Samoa, provided timed overnight urine specimens, and self-reported perceptions and behaviors associated with contributions to one's family, aiga, and chief, matai, and communal gift exchanges, fa'alavelave. Urinary norepinephrine and epinephrine excretion rates were measured by high performance liquid chromatography with electrochemical detection. Age (≤40 vs. >40 years) and gender-specific regression models were estimated to detect associations with catecholamine excretion.
Young women who contribute more to their matai, who consider fa'alavelave to be a financial strain, and who view their contribution to their matai to be "just right," had significantly higher residence-adjusted norepinephrine excretion. Young women who contribute more to their matai, who consider fa'alavelave to be a financial strain, and who consider their contribution to their aiga not to be a burden, had higher epinephrine excretion. Older men who contribute more to their aiga and who perceive their contribution to their aiga to be "just right" had increased residence-adjusted epinephrine excretion.
Individual-level perceptions and behaviors related to traditional socioeconomic obligations are a significant correlate of increased overnight catecholamine excretion rates. Higher excretion rates may be attributed to psychosocial stress arousal associated with a discordance between personal desires for upward social mobility, and family and community-based socioeconomic obligations. Changes in patterns of individual-level psychosocial stress arousal may contribute to cardiovascular disease risk in modernizing Samoans.
American Journal of Human Biology 09/2011; 23(5):693-702. · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: Atypical odontalgia (AO) is a chronic dentoalveolar pain condition of unknown etiology that may involve peripheral and central mechanisms. We used functional magnetic resonance imaging (fMRI) to identify cortical and subcortical activation patterns in AO and control subjects following dentoalveolar pressure stimuli. Methods: 13 AO (11 females; mean age 5510yrs, 12 right-handed) and 13 age-, gender- and handedness-matched control subjects received dentoalveolar pressure stimuli during fMRI using blood-oxygenation-level-dependent (BOLD) contrast (Siemens 3T Trio scanner; TR=3000ms; TR=30ms; voxel size=3x3x5.375mm; matrix size=64x64x36 voxels). Intraoral stimulation was delivered using a MR-compatible custom device (30s baseline, 3x 30s-ON/30s-OFF) over the reported dentoalveolar pain location for AO (8 right-sided) and to matched locations in controls. AO and controls received pressure stimulus evoking pain ratings between 3-5 in a 0/10 verbal scale (pain-lock), while only controls received a second stimulation level to match the mean pressure delivered for AO (stim-lock). Results: Brain activations overlapped for AO and controls (pain-lock), including primary/secondary somatosensory cortices, inferior parietal lobe, thalamus and cerebellum (see table/figure). Mean brain activation area for the AO group (306,662 mm3) was larger compared to controls (pain-lock=88,272 mm3; stim-lock=4,772mm3). AO group displayed significantly greater activation than controls for both stimulus levels, whilst controls had no greater activation than AO for either pain- or stim-lock stimuli. Conclusions: At non-painful stimulus level for controls, AO subjects had wider distribution of cortical and subcortical activation patterns than those consistent with reduced pain thresholds in AO patients. When stimulus was matched for subjective pain ratings, AO still presented greater brain activation than controls that overlap. Our findings suggest that AO subjects recruit more widespread brain pathways following dentoalveolar pressure stimuli compared to controls. Supported by grants K12-RR023247, P41-RR008079 and P30-NS057091.
[Show abstract][Hide abstract] ABSTRACT: Ecological and sociodemographic correlates of stress may contribute to cardiovascular disease risk in modernizing Samoans.
The effects of peri-urban vs rural residence, education, occupation, caffeine intake and cigarette consumption on urinary catecholamine excretion were studied in Samoan adults.
Five hundred and seven participants, aged 29-69 years, were randomly selected from nine villages throughout Samoa. Sociodemographic and lifestyle factors were assessed by questionnaire. Epinephrine and norepinephrine excretion rates were measured by high performance liquid chromatography with electrochemical detection in overnight urine samples. Age ( ≤ 40 vs >40 years) and gender-specific regression models were estimated to detect associations with BMI-adjusted catecholamine excretion.
Norepinephrine was significantly higher in peri-urban young men and older women. Epinephrine was significantly higher in peri-urban older men. Adjustment for caffeine attenuated the relationship between residence and norepinephrine in young women.
General residential exposure to modernization in urban villages is a significant correlate of increased overnight catecholamine excretion rates and is consistent with past studies. Caffeine consumption in younger women plays a complex role in stress-related catecholamine excretion. Further studies of individual level attitudinal and behavioural factors in Samoans are needed to understand psychosocial stress, physiologic arousal and health.
Annals of Human Biology 03/2011; 38(2):137-45. · 1.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pain in the temporomandibular joint (TMJ) region often occurs with no overt signs of injury or inflammation. Although the etiology of TMJ-related pain may involve multiple factors, one likely risk factor is female gender or estrogen status. Evidence is reviewed from human and animal studies, supporting the proposition that estrogen status acts peripherally or centrally to influence TMJ nociceptive processing. A new model termed the "TMJ pain matrix" is proposed as critical for the initial integration of TMJ-related sensory signals in the lower brainstem that is both modified by estrogen status, and closely linked to endogenous pain and autonomic control pathways.
International Review of Neurobiology 01/2011; 97:251-84. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The interior structures of the eye are well supplied by the trigeminal nerve; however, the function of these afferent fibers is not well defined. The aim of this study was to use c-fos like immunohistochemistry (Fos-LI) to map the trigeminal brainstem complex after intravitreal microinjection or ocular surface application of capsaicin, a selective transient receptor potential vanilloid 1 (TRPV1) agonist in male rats under barbiturate anesthesia. The effect of ocular inflammation on Fos-LI was tested 2 or 7 days after UV irradiation of the eye. In non-inflamed controls, intravitreal capsaicin produced peaks of Fos-LI at the trigeminal subnucleus interpolaris/caudalis (Vi/Vcvl) transition and in superficial laminae at the caudalis/upper cervical cord (Vc/C1) junction regions. At the Vc/C1 junction intravitreal capsaicin induced Fos-LI in a dose-dependent manner, while at the Vi/Vcvl transition responses were similar after vehicle or capsaicin injections. Two days, but not 7 days, after UV irradiation intravitreal and ocular surface capsaicin-evoked Fos-LI at the Vc/C1 junction and nucleus tractus solitarius (NTS) were markedly enhanced, whereas the responses at the Vi/Vcvl transition were not different from non-inflamed controls. More than 80% of trigeminal ganglion neurons labeled after intravitreal microinjection of Fluorogold also expressed immunoreactivity for the TRPV1 receptor. These findings suggested that most intraocular trigeminal sensory nerves serve as nociceptors. The similar pattern and magnitude of Fos-LI after capsaicin suggested that TRPV1-responsive trigeminal nerves that supply intraocular and ocular surface tissues form a unified integrative circuit in the caudal brainstem. Intensity coding of capsaicin concentration and facilitation of Fos-LI expression after UV irradiation strongly supported the hypothesis that the Vc/C1 junction was critical for nociceptive processing related to ocular pain, whereas the Vi/Vcvl transition region likely served other functions in ocular homeostasis under naïve and inflamed conditions.
[Show abstract][Hide abstract] ABSTRACT: Few methods exist to study central nervous system processes following dentoalveolar tactile stimulation using functional magnetic resonance imaging (fMRI), likely due to inherent technical difficulties. Our primary goal was to develop and perform feasibility testing of a novel device capable of delivering valid and reliable dentoalveolar stimuli at dental chair-side and during MRI. Details of a device designed to deliver dentoalveolar dynamic pressure stimuli are described. Device testing took place in three settings: a) laboratory testing to assess range of stimulus force intensities, b) dental chair-side to assess reliability, validity and discriminant ability in force-pain relationship; and c) MRI to evaluate magnetic compatibility and ability to evoke brain activation in painfree subjects similar to those described in the literature.
A novel device capable of delivering valid and reliable dentoalveolar somatosensory stimulation was developed (ICC = 0.89, 0.78-1 [95% CI]). Psychophysical data analysis showed high discriminant ability in differentiating painfree controls from cases with chronic dentoalveolar pain related to deafferenting dental procedures (sensitivity = 100%, specificity = 86.7%, area under ROC curve = 0.99). FMRI results of dentoalveolar dynamic pressure pain in painfree subjects revealed activation of brain areas typically associated with acute pain processing including thalamus, primary/secondary somatosensory, insular and prefrontal cortex.
A novel psychophysical method to deliver dynamic dentoalveolar pressure stimulation was developed and validated, allowing non-invasive MRI-based exploration of central nervous system function in response to intraoral somatosensation.
The organization of the trigeminal system is unique as it provides somatosensory innervation to the face, masticatory and oral structures, the majority of the intracranial contents 1 and to specialized structures (tongue, nasal mucosa, auricle, tympanic membrane, cornea and part of the conjunctiva) 2. Somatic sensory information transmitted by the trigeminal nerve is crucial for normal orofacial function; however, the mechanisms of many chronic pain conditions affecting areas innervated by this sensory system are not well understood 345. The clinical presentation of chronic intraoral pain in the area of a tooth or in a site formally occupied by a tooth with no clinical or radiological signs of pathology, referred to as atypical odontalgia (AO) 67, is one such chronic pain condition of particular interest to dentists that is difficult to diagnose and manage. Recent research suggests both peripheral and central nervous system mechanisms being involved in AO pathophysiology 8910, but the majority of mechanism-based research of patients with AO has focused on the "peripheral aspect" 7.Functional magnetic resonance imaging (fMRI) is an established research technique to study the central aspects of pain 11. Of existing neuroimaging techniques, fMRI provides good spatial resolution of cortical and subcortical structures critical in the processing of nociception, acceptable temporal resolution, does not involve ionizing radiation, and can be performed using most MRI systems that already exist in research centers and the community. For these reasons, we sought to develop a protocol that allows us to use this tool to investigate the central mechanisms involved in the processes of intraoral pain arising from the dentoalveolar region. Using this device, our long-term objective is to improve our understanding of the underlying mechanisms of persistent dentoalveolar pain.In the past few years several studies used fMRI to investigate the human trigeminal system 1213, with a limited subset focusing on intraoral stimulation - specifically on the dentoalveolar processes, such as lip, tongue and teeth stimulation 14 or only teeth 151617. Some reasons for scarce literature on this topic may be the technical challenges involved in delivering facial/intraoral stimulation inside a MR scanner 1718: possibility of magnetic interference, detriment of image quality, subject discomfort and reduced working space between the subject's head and the radiofrequency coil. As a consequence a MR-compatible device would need to not only overcome these challenges but also be capable of delivering a controlled and reproducible stimuli 19, as reliability/reproducibility is a necessary feature of sensory testing 20.Existing MR-compatible methods of dentoalveolar stimulation are limited and do not adequately deliver stimuli across a range of non-painful to painful intensities and/or cannot be adjusted to reach posterior aspects of the dentoalveolar region. Therefore our goal was to develop and test the feasibility of a device able to: 1) provide reliable and valid dentoalveolar stimuli, 2) deliver such stimulation within the restricted space of an MR head coil, 3) be compatible for use within an MR environment, and 4) produce brain activation in painfree controls consistent to those observed by others using fMRI.
[Show abstract][Hide abstract] ABSTRACT: Psychological stress and estrogen status are risk factors to develop painful temporomandibular joint disorders (TMJD); however, the neural basis for this relationship is not known. This study tested the hypothesis that repeated forced swim stress and estradiol treatment alter the phosphorylation of cAMP responsive element-binding protein (pCREB) in trigeminal subnucleus caudalis (Vc), the initial site of sensory input from the TMJ. Ovariectomized female rats were given low or high dose estradiol and subjected to repeated forced swim stress for 3 days and on day 4 an intra-TMJ injection of mustard oil or vehicle was given. Forced swim alone increased the number of pCREB-positive neurons, independent of estradiol treatment or TMJ stimulation, in superficial and deep laminae of Vc. Forced swim also increased the number of Fos-positive neurons in superficial laminae and neurokinin-1 receptor mRNA in whole dorsal Vc, independent of estradiol treatment. These results indicated that persistent psychophysical stress alone was sufficient to increase the expression of pCREB and downstream regulated genes associated with enhanced excitability in the caudal medullary dorsal horn, a brainstem region thought to be critical for TMJD pain.