Teppei Sago

Central glial activation mediates cancer-induced pain in a rat facial cancer model

Peripheral and central glial activation plays an important role in development of pain hypersensitivity induced by inflammation and nerve injury. However, the involvement of glial cells in cancer pain is not well understood. The present study evaluated the peripheral and central glial activation and the effect of an inhibitor of glial activation, propentofylline, on pain-related behaviors in a rat facial cancer model of the growth of Walker 256B cells in the unilateral vibrissal pad until days 3-4 post-inoculation. As compared with sham animals, the facial grooming period was prolonged, the withdrawal latency to radiant heat stimulation was shortened, and the withdrawal threshold by von Frey hair stimulation was decreased at the inoculated region, indicating the development of spontaneous pain, thermal hyperalgesia and mechanical allodynia. In immunostainings for Iba1 and glial fibrillary acidic protein (GFAP), although there were no morphological changes of GFAP-immunopositive satellite glial cells in the trigeminal ganglion, Iba1-immunopositive microglia and GFAP-immunopositive astrocytes in the medullary dorsal horn showed large somata with cell proliferation. After the daily i.p. administration of propentofylline beginning pre-inoculation, the central glial activation was attenuated, the prolonged facial grooming was partially suppressed, and the induced allodynia and hyperalgesia from day 2 were prevented, without a change in tumor size. These results suggest that glial activation in the CNS, but not in the peripheral nervous system, mediates the enhancement of spontaneous pain and the development of allodynia and hyperalgesia at an early stage in the facial cancer model.

Endothelin Receptor-mediated Responses in Trigeminal Ganglion Neurons

Recent evidence implicates endothelin in nociception, but it is unclear how endothelin activates trigeminal ganglion (TRG) neurons. In the present study, we investigated the expression of the endothelin receptors ETA and ETB and endothelin-induced responses in rat TRG neurons. Double-immunofluorescence studies demonstrated that ETA and ETB were expressed in TRG neurons and that 26% of ETA- or ETB-expressing neurons expressed both receptors. During whole-cell patch-clamp recording, endothelin-1 enhanced an induced current in response to capsaicin, a TRPV1 agonist, in approximately 20% of dissociated neurons. The enhancement was blocked by the PKC inhibitor chelerythrine and by the ETA antagonist BQ-123, but not by the ETB antagonist BQ-788. Ca2+-imaging showed that endothelin-1 increased the intracellular Ca2+ concentration in more than 20% of the dissociated neurons. Importantly, unlike the effect of endothelin-1 on capsaicin-induced current, the Ca2+ response was largely suppressed by BQ-788 but not by BQ-123. These results suggest that ETA-mediated TRPV1 hyperactivation via PKC activation and ETB-mediated Ca2+ mobilization occurs in different subsets of TRG neurons. These endothelin-induced responses may contribute to the induction of orofacial pain. The ETB-mediated function in TRG neurons is a special feature in the trigeminal system because of no ETB expression in dorsal root ganglion neurons.

Distinct time courses of microglial and astrocytic hyperactivation and the glial contribution to pain hypersensitivity in a facial cancer model.

Although recent evidence suggests that central glial hyperactivation is involved in cancer-induced persistent pain, the time course of this hyperactivation and the glial contribution to pain hypersensitivity remain unclear. The present study investigated the time-dependent spatial changes of microglial and astrocytic hyperactivation in the trigeminocervical complex, which consists of the medullary (MDH) and upper cervical (UCDH) dorsal horns, and pain-related behaviors in a rat facial cancer model in which Walker 256B-cells are inoculated into the vibrissal pad. In this model, the tumors grew within the vibrissal pad, from which sensory nerve fibers project into the MDH, but did not expand into the infraorbital region, from which fibers project into the UCDH. Nevertheless, mechanical allodynia and thermal hyperalgesia were observed not only in the vibrissal pad but also in the infraorbital region. Western blotting and immunofluorescence studies indicated that microglia were widely activated in the trigeminocervical complex on day 4 and gradually inactivated by day 11. In contrast, astrocytes were only activated in the MDH on day 4; the hyperactivation later expanded into the UCDH. Daily administration of the glial hyperactivation inhibitor propentofylline beginning on day 4 suppressed the glial hyperactivation on later days. Propentofylline treatment largely prevented allodynia/hyperalgesia in the infraorbital region beginning on day 5, although established allodynia/hyperalgesia in the vibrissal pad was less sensitive to the treatment. These results suggest that central glial hyperactivation, transient microglial hyperactivation and persistent astrocytic hyperactivation, contributes to the development of pain hypersensitivity but not to the maintenance of pain in this model.

Anesthetic Management of a Patient With Takayasu Arteritis

Takayasu arteritis is a rare chronic progressive panendarteritis involving the aorta and its main branches. Anesthesia in patients with this disease can be complicated by severe uncontrolled hypertension, end-organ dysfunction, and stenosis of major blood vessels. In this case, general anesthesia was induced with sevoflurane and remifentanil without complications. To prevent intraoperative complications, we conducted intubation with a rigid video laryngoscope with careful consideration of the concentrations of analgesics and sedatives used. This case demonstrates the importance of anesthetic techniques for maintaining adequate tissue perfusion without hemodynamic changes in the anesthetic management of patients with Takayasu arteritis.

[EXPRESS] Prostanoid-dependent spontaneous pain and PAR2-dependent mechanical allodynia following oral mucosal trauma: involvement of TRPV1, TRPA1 and TRPV4

During dental treatments, intraoral appliances frequently induce traumatic ulcers in the oral mucosa. Such mucosal injury-induced mucositis leads to severe pain, resulting in poor quality of life and decreased cooperation in the therapy. To elucidate mucosal pain mechanisms, we developed a new rat model of intraoral wire-induced mucositis and investigated pain mechanisms using our proprietary assay system for conscious rats. A thick metal wire was installed in the rats between the inferior incisors for one day. In the mucosa of the mandibular labial fornix region, which was touched with a free end of the wire, traumatic ulcer and submucosal abscess were induced on day 1. The ulcer was quickly cured until next day and abscess formation was gradually disappeared until five days. Spontaneous nociceptive behavior was induced on day 1 only, and mechanical allodynia persisted over day 3. Antibiotic pretreatment did not affect pain induction. Spontaneous nociceptive behavior was sensitive to indomethacin (cyclooxygenase inhibitor), ONO-8711 (prostanoid receptor EP1 antagonist), SB-366791, and HC-030031 (TRPV1 and TRPA1 antagonists, respectively). Prostaglandin E2 and 15-deoxyΔ12,14-prostaglandin J2 were upregulated only on day 1. In contrast, mechanical allodynia was sensitive to FSLLRY-NH2 (protease-activated receptor PAR2 antagonist) and RN-1734 (TRPV4 antagonist). Neutrophil elastase, which is known as a biased agonist for PAR2, was upregulated on days 1 to 2. These results suggest that prostanoids and PAR2 activation elicit TRPV1- and TRPA1-mediated spontaneous pain and TRPV4-mediated mechanical allodynia, respectively, independently of bacterial infection, following oral mucosal trauma. The pathophysiological pain mechanism suggests effective analgesic approaches for dental patients suffering from mucosal trauma-induced pain.

Comparison of pain tolerance thresholds of upper limb to identify the most appropriate venipuncture site.

PURPOSE Venipuncture is often accompanied by pain, which can compromise dental care and foment distrust toward dental care providers. The aim of the present study was to identify sites on the forearm and hand that have the greatest pain tolerance threshold (PTT) during venipuncture. MATERIALS AND METHODS The PTT was estimated in 20 healthy volunteers using a noninvasive nerve conduction threshold device. The subjects self-stimulated 5 sites (median cubital vein, cephalic vein at the cubitus, basilic vein, cephalic vein at the carpus, and superficial dorsal vein) at 2 kHz, 250 Hz, and 5 Hz. We measured the stimulation intensity before the subject deactivated the device. Differences in the average PTT values at each site were compared using the Kruskal-Wallis and Scheffé tests. P <.05 was considered to indicate statistical significance. RESULTS The PTT was significantly greater at the superficial dorsal vein than at the basilic vein for all 3 noninvasive nerve conduction threshold frequencies (P < .05). The estimated PTT was significantly greater at the superficial dorsal vein than at the median cubital vein and cephalic vein at the carpus in response to 250-Hz stimulation (P < .05). CONCLUSIONS The greater PTT of the superficial dorsal vein suggests that venipuncture at this site should result in the lowest pain intensity among all upper limb sites.

Characteristics of diffusion-weighted images and apparent diffusion coefficients of ranulas and other masses in and around the floor of the mouth

OBJECTIVE The aim of this study was to evaluate the characteristics of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values of ranulas. In addition, to elucidate DWI findings and ADC values of other representative masses in and around the floor of the mouth. STUDY DESIGN DWI findings and ADC values in 35 patients with ranulas and 33 patients with other masses were retrospectively reviewed with a central focus on cystic masses or lesions that may have cyst-like components in and around the floor of the mouth based on the diagnosis of each respective disease. RESULTS Ranulas were all well-defined, homogeneous masses with high signal intensity on DWI. The mean ± standard deviation ADC value of the 35 ranulas was 2.59 ± 0.31 × 10-3 mm2/s. There was a significant difference in ADC values between simple and plunging ranulas. On DWI, most other masses were heterogeneous, and most ADC values, except those for thyroglossal duct cysts, hemangiomas, and pleomorphic adenomas, were significantly lower than those for ranulas. CONCLUSIONS The characteristic DWI and ADC findings of ranulas can be determined accurately, and these data can be significantly useful in the differential diagnosis of many kinds of diseases in and around the oral floor.

Sedation With a Combination of Dexmedetomidine and Midazolam for Pediatric Dental Surgery

Intravenous sedation (IVS) is commonly used to complete dental treatment for uncooperative pediatric patients. Propofol (PRO) is widely used for IVS because of its short context sensitive half-time and amnestic effect. However, administering PRO to patients who have a history of egg anaphylaxis is still somewhat controversial. The evidence that supports the potential risks for allergic reactions following PRO use in patients with egg allergies is limited with some anesthesiologists recommending against its use in these patients. Alternative drug regimens for procedural sedation in this population are therefore desirable. Dexmedetomidine (DEX), a selective α-2 agonist, has antianxiety and sedative properties and has been widely used not only for procedural sedation with mild inhibitory effects on respiration but also during minor surgeries for its analgesic effect. In this paper, we describe the successful administration of a combination of DEX and low-dose midazolam (MDZ) for sedation in an uncooperative pediatric patient. Both DEX and MDZ have been reported as safe and useful sedatives for dental treatment, and their combination may provide a helpful option for IVS of pediatric patients for whom PRO is not preferred.

Effect of sweet solutions on pain tolerance threshold in pediatric oral mucosa

Abstract Purpose We examined the effects of sweet taste stimulation on pain tolerance threshold (PTT) of oral mucosa in children. Subjects and methods Subjects comprised 10 children (mean age, 7.3±1.2 years) for whom PTT of oral mucosa was measured 2min after oral administrations of sucrose or xylitol and water. Sine wave current stimulation (2kHz, 250Hz and 5Hz, SWCS) which can stimulate sensory nerve fiber selectively (A β , A δ and C) was used to measure PTT. Results Sweet taste stimulation with sucrose or xylitol increased oral mucosa PTT in children, but not in adults. No difference in the increased PTT was seen between sucrose and xylitol. Conclusions Oral administration of sucrose and xylitol may potentially relieve pain associated with local anesthetic injections in children.

Glial activation in the medullary dorsal horn and its contributions to cancer-induced pain in a rat facial cancer model

The development of pain after peripheral nerve and tissue injury involves not only neuronal pathways but also glia. However, uncertainty still remains as to the relative contribution of different types of glial cells in the development of the pain-related enhanced response states. We examined the contribution of glial cells to the central sensitization in the rat spinal dorsal horn which is induced in neuropathic pain and inflammatory pain. In rats subjected to neuropathic pain, the immunoreactivity (IR) of microglial marker OX 42 was largely increased. In rats subjected to inflammatory pain, IR of astosytes marker GFAP was slightly increased. The optically-recorded neuronal excitation induced by single-pulse stimulation to the dorsal root was augmented in rats subjected to neuropathic pain and rats subjected to inflammatory pain by comparison to control rats. The bath application of a microglial inhibitor minocycline and a p38 mitogen-activated protein kinase inhibitor SB203580 inhibited the neuronal excitation in rats subjected to neuropathic pain, but not in control and rats subjected to inflammatory pain. PPADS slightly inhibited the neuronal excitation in all group. The additional perfusion of TNP-ATP in PPADS largely inhibited the neuronal excitation in rats subjected to neuropathic pain. In contrast, an astroglial toxin L-alpha-aminoadipate and a gap junction blocker carbenoxolone inhibited the neuronal excitation in rats subjected to inflammatory pain, but not in control and rats subjected to neuropathic pain. The larger number of cells in the spinal cord slice taken from rats subjected to neuropathic pain showed the Ca2+ signal by puff application of ATP to comparison with control and rats subjected to inflammatory pain. The Ca2+ signal was inhibited by minocycline and TNP-ATP. Research fund: KAKENHI22600005.