Microneedles Coated with Tramadol Exhibit Antinociceptive Effect in a Rat Model of Temporomandibular Hypernociception.

Coated microneedles have emerged as a promising drug delivery system for inflammatory pain treatment. We have previously shown that tramadol injection into the rat temporomandibular joint (TMJ) induces an antinociceptive and anti-inflammatory effect. In this study, microneedles coated with tramadol were investigated as a platform to treat TMJ pain. Male Wistar rats were administered tramadol using an intra-TMJ injection or with microneedles coated with tramadol, followed by 1.5% formalin nociceptive challenge administered 15 minutes later. The nociceptive behavior of rats was evaluated, and their periarticular tissues were removed after euthanasia for analysis. The duration of antinociceptive effect was determined by performing the formalin challenge at different time points extending up to 6 days post tramadol administration. Microneedles coated with tramadol produced an antinociceptive effect similar to injection of tramadol into the rat TMJ. Surprisingly, tramadol delivery using coated microneedles produced a more durable antinociceptive effect lasting as much as 2 days post tramadol delivery as compared with an antinociceptive effect lasting under 2 hours from intra-TMJ injection of tramadol. The proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß (IL-1ß) were found to be reduced, whereas the anti-inflammatory cytokine IL-10 was found to be elevated in tramadol-treated groups. In conclusion, microneedles coated with tramadol can offer a therapeutic option for pain control of inflammatory disorders in the TMJ.

Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ.

BACKGROUND: Temporomandibular disorders (TMDs) have the highest prevalence in women of reproductive age. The role of estrogen in TMDs and especially in TMDs related pain is not fully elucidated. Voltage-gated sodium channel 1.7 (Nav1.7) plays a prominent role in pain perception and Nav1.7 in trigeminal ganglion (TG) is involved in the hyperalgesia of inflamed Temporomandibular joint (TMJ). Whether estrogen could upregulate trigeminal ganglionic Nav1.7 expression to enhance hyperalgesia of inflamed TMJ remains to be explored. METHODS: Estrous cycle and plasma levels of 17ß-estradiol in female rats were evaluated with vaginal smear and enzyme linked immunosorbent assay, respectively. Female rats were ovariectomized and treated with 17ß-estradiol at 0 µg, 20 µg and 80 µg, respectively, for 10 days. TMJ inflammation was induced using complete Freund's adjuvant. Head withdrawal thresholds and food intake were measured to evaluate the TMJ nociceptive responses. The expression of Nav1.7 in TG was examined using real-time PCR and western blot. The activity of Nav1.7 promoter was examined using luciferase reporter assay. The locations of estrogen receptors (ERα and ERß), the G protein coupled estrogen receptor (GPR30), and Nav1.7 in TG were examined using immunohistofluorescence. RESULTS: Upregulation of Nav1.7 in TG and decrease in head withdrawal threshold were observed with the highest plasma 17ß-estradiol in the proestrus of female rats. Ovariectomized rats treated with 80 µg 17ß-estradiol showed upregulation of Nav1.7 in TG and decrease in head withdrawal threshold as compared with that of the control or ovariectomized rats treated with 0 µg or 20 µg. Moreover, 17ß-estradiol dose-dependently potentiated TMJ inflammation-induced upregulation of Nav1.7 in TG and also enhanced TMJ inflammation-induced decrease of head withdrawal threshold in ovariectomized rats. In addition, the estrogen receptor antagonist, ICI 182,780, partially blocked the 17ß-estradiol effect on Nav1.7 expression and head withdrawal threshold in ovariectomized rats. ERα and ERß, but not GPR30, were mostly co-localized with Nav1.7 in neurons in TG. In the nerve growth factor-induced and ERα-transfected PC12 cells, 17ß-estradiol dose-dependently enhanced Nav1.7 promoter activity, whereas mutations of the estrogen response element at -1269/-1282 and -1214/-1227 in the promoter completely abolished its effect on the promoter activity. CONCLUSION: Estradiol could upregulate trigeminal ganglionic Nav1.7 expression to contribute to hyperalgesia of inflamed TMJ.

Bilateral increases in ERK activation at the spinomedullary junction region by acute masseter muscle injury during temporomandibular joint inflammation in the rats.

We determined the role of persistent monoarthritis of temporomandibular joint region (TMJ) on bilateral masseter muscle (MM) nociception in male rats using orofacial nocifensive behaviors, phosphorylated extracellular signal-regulated kinase and Fos induction at the trigeminal subnucleus caudalis/upper cervical spinal cord (Vc/C2) region in response to formalin injection to the MM region. TMJ inflammation was induced by local injection of CFA into the left TMJ region. Orofacial nocifensive behaviors evoked by formalin injection ipsilateral or contralateral to the TMJ inflammation appeared to be increased at 1-14 days or at 1, 10 and 14 days after induction of TMJ inflammation, respectively, while increases in behavioral duration were seen mainly in the late phase rather than the early phase. The number of pERK positive cells was investigated in superficial laminae at the Vc/C2 region at 3, 10, 20, 60 and 80 min after MM stimulation with formalin at 14 days after TMJ inflammation. TMJ-inflamed rats displayed greater responses of pERK expression by the ipsilateral MM stimulation at 3-60 min, while contralateral MM stimulation increased pERK expression at 3, 10 and 20 min compared to non-CFA rats. Fos expression by MM stimulation was increased at 14 days after induction of TMJ inflammation regardless of the affected side. These findings showed that persistent TMJ inflammation for 10 and 14 days is sufficient to enhance MM nociception indicated by behaviors and neural responses in superficial laminae at the Vc/C2 region.

Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion.

Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, the therapy-refractoriness of its pain, and its largely elusive pathogenesis. Against this background, we sought to investigate the pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation-evoked pain behavior in mice and that trigeminal ganglion pronociceptive changes are TRPV4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4(-/-) mice with TMJ inflammation, attenuation of bite force was significantly less than in wildtype (WT) mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ inflammation and mandibular bony changes were apparent after injections of complete Freund adjuvant but were remarkably independent of the Trpv4 genotype. It was intriguing that, as a result of TMJ inflammation, WT mice exhibited significant upregulation of TRPV4 and phosphorylated extracellular-signal-regulated kinase (ERK) in TMJ-innervating trigeminal sensory neurons, which were absent in Trpv4(-/-) mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed resistance to reduction of bite force similar to that of Trpv4(-/-) mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ inflammation and probably functions upstream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in vivo. TRPV4 therefore represents a novel pronociceptive target in TMJ inflammation and should be considered a target of interest in human TMJD.

Local blockade of integrins in the temporomandibular joint region reduces Fos-positive neurons in trigeminal subnucleus caudalis of female rats produced by jaw movement.

This study assessed the influence of integrins on trigeminal brainstem neural activity evoked during jaw movement (JM). Limited range of motion and pain during jaw opening are common complaints of patients with temporomandibular joint (TMJ) disorders. JM (0.5 Hz, 30 min) was presented to ovariectomized (OvX) female rats given estrogen replacement and males under barbiturate anesthesia. Quantification of Fos-like immunoreactivity (Fos-LI) after JM served as an index of evoked neural activity. Rats were injected locally in the TMJ with either an active (GRGDS, 300 microM, 25 microl) or an inactive integrin antagonist (SDGRG) prior to JM. The effect of prior inflammation of the TMJ region was assessed in separate groups of rats by injecting bradykinin (10 microM, 25 microl) with or without integrin drugs prior to JM. Active integrin antagonist significantly reduced JM-evoked Fos-LI in superficial laminae at the trigeminal subnucleus caudalis/upper cervical cord (Vc/C2) junction in OvX compared to male rats independent of bradykinin pretreatment. Fos-LI produced in the dorsal paratrigeminal and trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition regions was not reduced by active integrin antagonist in males or OvX females. Active integrin antagonist did not affect Fos-LI produced after injection of bradykinin alone into the TMJ. These results suggest that RGD binding integrins contribute to JM-evoked neural activity at the Vc/C2 junction under naive and inflamed conditions in a sex-dependent manner.

MRS assessment of glutamate clearance in a novel masticatory muscle pain model.

The injection of 1.0 M glutamate into the masseter (jaw-closer) muscle results in a short period of muscle pain (5-10 min) and a prolonged period of mechanical sensitization (> 30 min). It is unclear, however, whether there is a temporal relationship between intramuscular glutamate concentration and either muscle pain or mechanical sensitization. In the present study, (1)H MRS and electrophysiological recording of masticatory muscle nerve fibers were performed in order to monitor glutamate clearance and nerve fiber activity, respectively, after injection of glutamate into rat masticatory muscles. Glutamate signal amplitude was found to decay rapidly (half-life t 1/2 = 108 +/- 42 s), and became indistinguishable from the baseline 10 min after the injection. Glutamate-evoked nerve fiber activity was also found to decay rapidly (t 1/2 = 76 +/- 28 s). These results suggest that glutamate clearance correlates well with the time course of glutamate-evoked muscle pain fiber discharge.

Meal pattern changes associated with temporomandibular joint inflammation/pain in rats; analgesic effects.

Establishing a valid animal model to study temporomandibular joint (TMJ) pain has proven extremely difficult. Using complete Freund's adjuvant (CFA) to induce TMJ inflammation, we recently showed that meal pattern analysis could be used as a noninvasive biological marker to study TMJ pain in an animal model. The purpose of this study was to further validate our animal model by determining whether aspects of CFA-induced TMJ inflammation/pain are reversed with ibuprofen (IBU) treatment. In the first trial, 48 male rats were used and in the second trial, 32 female ovariectomized rats, given 17beta-estradiol replacement, were used. The rats were assigned to one of four groups: control (CON-CON); control+IBU (CON+IBU); CFA-CON; and CFA+IBU. In the male trial, CFA injection (P<.01) caused TMJ swelling and chromodacryorrhea (CFA-CON); IBU eliminated these changes in the CFA+IBU group. Meal pattern analysis showed the pertinent CFA-induced change and the IBU effect was that meal duration was increased in the CFA-CON group (P<.01), but normal in the CFA+IBU-treated group on the first, but not second, day postinjection. In the female trial, CFA increased TMJ swelling, but did not cause significant chromodacryorrhea (CFA-CON); IBU eliminated swelling in the CFA+IBU group. Meal duration was increased (P<.01) in the CFA-CON group, but was normal in the CFA+IBU-treated group on both the first and second days postinjection. In both trials, interleukin-1beta (IL-1beta) levels were increased similarly in CFA-CON and CFA+IBU groups (P<.01). This study shows that CFA-induced TMJ inflammation/pain can cause changes in meal patterns (i.e., meal duration), which may be used as a behavioral marker for TMJ inflammation/pain.

Rheumatological complications associated with the use of indinavir and other protease inhibitors.

Several cases are reported of rheumatological pathology (temporomandibular dysfunction, frozen shoulder, Dupuytren's disease, and tendinitis) most probably related to the intake of indinavir in HIV positive patients. A survey using an anonymous questionnaire of 878 people with HIV infection treated with antiretroviral drugs suggests that other protease inhibitors may also cause arthralgia.

[The effects of tumor necrosis factor on rabbits' temporomandibular joint].

The histological changes of 16 rabbits' temporomandibular joints (TMJ) were studied after they had been injected with tumor necrosis factor (TNF). The results show that TNF can destroy the articular tissues. The changes are similar to those found in TMJ disturbance syndrome. With the finding that the TNF appears in the synovial fluids of TMJ DS, the authors consider that the changes of articular tissues in TMJ DS are related to the presence of TNF in the joints.

[Metoclopramide intolerance and oral manifestations]. / Intolérance au Métoclopramide et manifestations stomatologiques.

Metoclopramide is a widely used product, which can accidentally cause acute dyskinesia, of which several forms may be observed, including dysarthria, tetany, spasmophilia, false cerebral vascular insult, trismus, hysteriform spell.... In all those cases, one should think of giving an antiemetic and of properly orienting history-taking, thus avoiding a longer stay in hospital that would not be justified. This is demonstrated by two patients recently admitted into the department of maxillofacial surgery and stomatology with maxillofacial signs related with the adverse effects of this kind of drug.