Rumiko Uda

Allodynia evoked by intrathecal administration of prostaglandin E2 to conscious mice

&NA; We recently reported that intrathecal (i.t.) administration of prostaglandin (PG) F2&agr;. to conscious mice induced allodynia that was elicited by non‐noxious brushing of the flanks. In the presents study, we demonstrate that i.t. administration of PGD2 and PGE2 to conscious mice also results in allodynia. Dose dependency of PGD2 for allodynia showed a skewed bell‐shaped pattern (0.1 ng‐2.5&mgr;g&ohgr;use), and the maximal allodynic effect was observed with 1.0 &mgr;g at 15 min after intrathecal injection. PGD2induced allodynia showed a time course and dose dependency similar to that induced by PGF2&agr;, but with lower scores. On the other hand, dose dependency of PGE2 for allodynia showed a bell‐shaped pattern over a wide range of dosage from 10 fg to 2.0 &mgr;g/mouse. The maximal allodynic effect was observed with 0.01–0.1 &mgr;g at 5 min after i.t. injection, and the response gradually decreased over the experimental period of 50 min. Intrathecally administered strychnine and the GABA A antagonist bicuculline also induced allodynia in conscious mice. The time courses of allodynia evoked by strychnine and bicuculline coincided with those by PGE2 and PGF2&agr;, respectively. PGE2‐induccd allodynia was dose‐dependently relieved by the strychnine‐sensitive glycine receptor agonist taurine, the NMDA receptor antagonist kctamine, and a high dose of the &agr;2‐adrenergic agonist clonidine, but not by the GABAA agonist muscimol or by the GABAB agonist baclofen. In contrast, PGF2&agr;‐induced allodynia was dramatically inhibited by clonidine and baclofen, but not by taurine, ketamine or muscimol. In addition, PGE2&agr;‐induced hyperalgesia assessed by the hot plate test was not suppressed by taurine or clonidine. These results demonstrate that the mechanism of PGE2&agr;‐induced allodynia is different from that of PGF2‐induced allodynia and from that of PGE2&agr;‐induced hyperalgesia.

Nociceptive effects induced by intrathecal administration of prostaglandin D2, E2, or F2α to conscious mice

The effects of intrathecal administration of prostaglandins on pain responses in conscious mice were evaluated by using hot plate and acetic acid writhing tests. Prostaglandin D2 (0.5-3 ng/mouse) had a hyperalgesic action on the response to a hot plate during a 3-60 min period after injection. Prostaglandin E2 showed a hyperalgesic effect at doses of 1 pg to 10 ng/mouse, but the effect lasted shorter (3-30 min) than that of prostaglandin D2. Similar results were obtained by acetic acid writhing tests. The hyperalgesic effect of prostaglandin D2 was blocked by simultaneous injection of a substance P antagonist (greater than or equal to 100 ng) but not by AH6809, a prostanoid EP1-receptor antagonist. Conversely, prostaglandin E2-induced hyperalgesia was blocked by AH6809 (greater than or equal to 500 ng) but not by the substance P antagonist. Prostaglandin F2 alpha had little effect on pain responses. These results demonstrate that both prostaglandin D2 and prostaglandin E2 exert hyperalgesia in the spinal cord, but in different ways.

Characterization of EP-receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice.

1 Intrathecal (i.t.) administration of prostaglandin E2 (PGE2) to conscious mice induced allodynia, a state of discomfort and pain evoked by innocuous tactile stimuli, and hyperalgesia as assessed by the hot plate test. We characterized prostaglandin E receptor subtypes (EP1–3) involved in these sensory disorders by use of 7 synthetic prostanoid analogues. 2 Sulprostone (EP1 < EP3) induced allodynia over a wide range of dosages from 50 pg to 5 μg kg−1. The maximal allodynic effect was observed at 5 min after i.t. injection, and the response gradually decreased over the experimental period of 50 min. This sulprostone‐induced allodynia showed a time course similar to that induced by PGE2. 3 17‐Phenyl‐ω‐trinor PGE2 (EP1 > EP3) and 16,16‐dimethyl PGE2 (EP1 = EP2 = EP3) were as potent as PGE2 in inducing allodynia, and more potent than sulprostone. Butaprost (EP2), 11‐deoxy PGE1 (EP2 = EP3), MB 28767 (EP3), and cicaprost (prostaglandin I2 (IP‐) receptor) induced allodynia, but with much lower scores. 13,14‐Dihydro‐15‐keto PGE2, a metabolite of PGE2, did not induce allodynia. 4 16,16‐Dimethyl PGE2 as well as PGE2 induced hyperalgesia over a wide range of dosages (16,16‐dimethyl PGE2: 5 pg–0.5 μg kg−1 PGE2: 50 pg–0.5 μg kg−1) with two apparent peaks at 0.5 ng kg−1 and 0.5 μg kg−1. Sulprostone (EP1 < EP3) and 17‐phenyl‐ω‐trinor PGE2 (EP1 > EP3) showed a bell‐shaped hyperalgesia at lower doses of 5 pg–5 ng kg−1 and 50 pg–50 ng kg−1, respectively. MB 28767 (EP3) showed a monophasic hyperalgesic action over a wide range of dosages at 50 pg–5 μg kg−1. Butaprost (EP2) induced hyperalgesia at doses higher than 50 ng kg−1. 5 These results demonstrate that PGE2 may exert allodynia through the EP1‐receptor and hyperalgesia through EP2‐ and EP3‐receptors in the mouse spinal cord.

Involvement of glutamate receptors in allodynia induced by prostaglandins E2 and F2α injected into conscious mice

&NA; In order to investigate the involvement of glutamate receptor systems in allodynia induced by prostaglandin (PG) E2 or F2&agr;, we co‐administered antagonists for N‐methyl‐d‐aspartate (NMDA). non‐NMDA, or metabotropic glutamate receptors intrathecally with PGE2 or PGF2&agr; and examined their effects on the allodynia evoked in conscious mice by non‐noxious brushing of the flanks. MK‐801, a non‐competitive NMDA receptor channel blocker, and d‐AP‐5, a selective NMDA receptor antagonist, dose‐dependently blocked PGH2‐induced allodynia with an IC50 of 1.60 and 0.52 &mgr;g/mouse, respectively. A glycine binding‐site antagonist for the NMDA receptor, 7‐CI‐KYNA, did not influence it. None of these NMDA receptor antagonists inhibited PGF2&agr;‐evoked allodynia. Non‐NMDA receptor antagonists GAMS and CNQX inhibited both PGE2‐ and PGF2&agr;‐induced allodynia. On the other hand, l‐AP‐3 and l‐AP‐4, putative metabotropic glutamate receptor antagonists, dose‐dependently antagonized the allodynia induced by PGF2&agr; with an IC50 of 0.92 and 3.26 ng/mouse, respectively, but not that induced by PGE2. Intrathecal administration of l‐glutamate produced allodynia over a wide range of low doses from 0.1 pg to 0.1 &mgr;g/mouse, and the maximal effect was observed at 1 ng. Similar to allodynia induced by prostaglandins, the response lasted over a 50‐min experimental period. These results demonstrate that both PGE2‐ and PGF2&agr;‐evoked allodynia are mediated through a pathway that includes the glutamate receptor system but that subtypes of glutamate receptors involved and sites of action in the spinal cord may he different between them.

Effect of NMDA receptor antagonists on prostaglandin E2-induced hyperalgesia in conscious mice

Intrathecal (i.t.) injection of prostaglandin E2 (PGE2) to conscious mice produced a hyperalgesic action over a wide range of dosages with two apparent peaks at 100 pg and 10 ng per mouse, which may be mediated through EP3 and EP2 subtypes of the PGE receptor. In the present study, the effects of NMDA receptor antagonists on hyperalgesia induced by PGE2 were evaluated by the hot plate test at 30 min after i.t. injection. Hyperalgesia induced by a higher dose of PGE2 (10 ng/mouse) was relieved by D-AP5 (a competitive antagonist), 7-Cl-KynA (a glycine site antagonist), and ketamine and MK801 (non-competitive channel blockers). Intrathecal injection of butaprost (10 ng/mouse), an EP2 agonist, induced hyperalgesia, and this hyperalgesia was blocked by D-AP5, 7-Cl-KynA, ketamine, and MK801, similar to that induced by 10 ng of PGE2. On the other hand, hyperalgesia induced by a lower dose of PGE2 (100 pg/mouse) was blocked by D-AP5 and 7-Cl-KynA, but not by ketamine and MK801. Intrathecal injection of sulprostone (100 pg/mouse), an EP1 and EP3 agonist, induced hyperalgesia, and this hyperalgesia was blocked by D-AP5 and 7-Cl-KynA, but not by ketamine and MK801, similar to that induced by 100 pg of PGE2. These results first demonstrate that the NMDA receptor is involved in the PGE2-induced hyperalgesia and suggest that the hyperalgesic action by lower and higher doses of PGE2 may be mediated through EP3 and EP2 subtypes, respectively.

The influence of head and neck position on ventilation with the i-gel airway in paralysed, anaesthetised patients.

Context and objective We hypothesised that head and neck position could affect the effectiveness of ventilation with the i-gel airway. To test this hypothesis, we investigated the influence of different head and neck positions on oropharyngeal sealing pressures and ventilation scores during ventilation with i-gel. Methods A single, experienced supraglottic airway device user inserted the i-gel in 20 paralysed, anaesthetised patients who were scheduled for oral surgery. Oropharyngeal leak pressures and ventilation scores were measured with the head and neck in the neutral position, flexed, extended or rotated to the right. Ventilation was scored from 0 to 3 based on three criteria (no leakage with an airway pressure of 15 cmH2O, bilateral chest excursion and a square wave capnogram; each item scoring 0 or 1 point). Results Compared with the neutral position (25.8 ± 5.2 cmH2O), oropharyngeal leak pressure was significantly higher with flexion (28.5 ± 3.4 cmH2O, P = 0.015) and lower with extension (23.0 ± 4.2 cmH2O, P = 0.015), but similar with rotation (26.7 ± 5.1 cmH2O, P = 0.667). Flexion of the head and neck [2 (1–3)] adversely affected the ventilation score compared with the neutral position [3 (2–3), P = 0.004]. Conclusion Effective ventilation with an i-gel can be performed in patients in whom the head and neck is extended or rotated, whereas flexion of the head and neck adversely affects ventilation. Clinically, flexion of the head and neck should be avoided during ventilation with the i-gel.

Damaged Univent tubes.

The patient was a 62-yr-old, 158-cm, 58-kg man scheduled for surgery with a diagnosis of esophageal cancer. After placement of a 8.5-mm single-lumen cuffed Univent@ tube made of silicon, the built-in cuff was advanced into the right mainstem bronchus with the aid of fiberoptic bronchoscopy. The bronchial blocker cuff was inflated to permit one-lung ventilation that was confirmed by auscultation of the lungs. The patient was in a left semilateral decubitus position, and the operating table was rotated to the left according to the surgical procedure. During two-lung ventilation, analysis of arterial blood gases was normal, and pulse oximetry showed 99%-100% oxygen saturation. However, during one-lung ventilation, oxygen saturation decreased to 93%, and Pao, gradually decreased from 130 to 52 mmHg despite the inhalation of 100% oxygen. One-lung ventilation time was 90 min in total, and during this period, both lungs were ventilated manually a few times until oxygen saturation recovered to 100%. Surgery was completed in 6 h 20 min; the anesthesia time was 7 h 40 min. The patient entered the intensive care unit with the Univent@ endotracheal tube still in place. When the trachea was suctioned, using a fiberoptic bronchoscope, we found a foreign body at the proximal region of the left anterior segmental bronchus, and the object was removed. As it seemed to be a silicon fragment, the Univent@ endotracheal tube was replaced with a singlelumen tube, and we inspected the Univent@ tube carefully. The inner part where a slip joint (a tracheal tube connector) attached to the tube was broken, and the object that was removed from the patient’s bronchus fit perfectly into the defective area (Fig. 1). Neither atelectasis nor the foreign object was seen on chest radiograph taken immediately after the patient entered the intensive care unit.

Optimal Degree of Mouth Opening for Laryngeal Mask Airway Function During Oral Surgery

PURPOSE This study was performed to determine the optimal degree of mouth opening in anesthetized patients requiring laryngeal mask airway (LMA) during oral surgery. PATIENTS AND METHODS A single, experienced LMA user inserted the LMA in 15 patients who were scheduled for elective oral surgery. Oropharyngeal leak pressure, intracuff pressure, and fiberoptic assessment of the LMA position were sequentially documented in 5 mouth conditions-opening of 1.4 (neutral position), 2, 3, 4, and 5 cm-and any resulting ventilatory difficulties were recorded. RESULTS Oropharyngeal leak pressure with the mouth open 4 cm (21.8 ± 3.2 cm H(2)O, P = .025) and 5 cm (27.3 ± 7.2 cm H(2)O, P < .001) was significantly higher than in the neutral position (18.1 ± 1.5 cm H(2)O), as was intracuff pressure (neutral position, 60.0 ± 0 cm H(2)O; 4 cm, 72.6 ± 5.1 cm H(2)O [P < .001]; and 5 cm, 86.9 ± 14.4 cm H(2)O [P < .001]). LMA position, observed by fiberoptic bronchoscopy, was unchanged by mouth opening, being similar in the 5 mouth conditions (P = .999). In addition, ventilation difficulties (abnormal capnograph curves or inadequate tidal volume) occurred in 2 of 15 patients (13%) and 7 of 15 patients (53%) (P < .001) with the mouth opening of 4 and 5 cm, respectively. CONCLUSIONS This study showed that a mouth opening over 4 cm led to substantial increases in oropharyngeal leak pressure and intracuff pressure of the LMA, warranting caution, because gastric insufflation, sore throat, and ventilation difficulties may occur. A mouth opening of 3 cm achieves acceptable airway conditions for anesthetized patients requiring LMA.

The Influence of Mouth Opening on Oropharyngeal Leak Pressure, Intracuff Pressure, and Cuff Position With the Laryngeal Mask Airway

PURPOSE The aim of this study was to investigate the influence of mouth opening on oropharyngeal leak pressure, intracuff pressure, and cuff position of the laryngeal mask airway (LMA). PATIENTS AND METHODS Fifteen patients who were scheduled for elective oral surgery were recruited into this study. A single, experienced LMA user inserted the LMA according to the manufacturers recommended technique. Oropharyngeal leak pressure, intracuff pressure, and fiberoptic assessment of the LMA position were documented under 3 mouth conditions: neutral position (1.4-cm distance between upper and lower incisors), mouth open (5- to 6-cm distance between upper and lower incisors), and return to the neutral position. Any ventilation difficulties under the 3 mouth conditions were recorded. RESULTS Oropharyngeal leak pressure with the mouth open was higher than in the neutral position (P < .001). Compared with the neutral position, intracuff pressure was also higher with the mouth open (P < .001). Both measurement values returned to control levels when the neutral position was once again assumed. The LMA position observed by fiberoptic bronchoscopy was unchanged by mouth opening and was similar in the 3 mouth conditions (P = .998). Although ventilatory difficulties occurred after mouth opening in 8 of 15 patients (P < .001), it did not occur when the neutral position was reassumed. CONCLUSIONS This study showed that mouth opening led to substantial increases in oropharyngeal leak pressure and intracuff pressure of the LMA, warranting caution because gastric insufflation, sore throat, and ventilation difficulties may occur.

Selective brain hypothermia suppresses noxious-evoked movement in canines

Systemic hypothermia suppresses noxious-evoked movement, but its main site of action is unknown. We examined the effect of hypothermia in the brain on noxious-evoked movement by selectively cooling the brain. Sixteen beagles were randomly divided into two groups and anesthetized with isoflurane/oxygen. After being deeply anesthetized, the dogs’ lungs were artificially ventilated, and several major vessels were cannulated for perfusion and monitoring. Cold lactate Ringer’s solution was infused into the right vertebral artery to cool the brain while maintaining the trunk temperature relatively warmer. When the brain temperature decreased to 20°C or 25°C, isoflurane administration was discontinued; the trunk temperatures at this stage were approximately 34.7°C and 34.6°C, respectively. After the end-tidal isoflurane concentration reached 0%, the base of the tail was stimulated with an electric current through 2 25-gauge needles. None of the dogs reacted to tail stimulation when the brain temperature was at 20°C, whereas 7 of 8 reacted at 25°C. These results indicate that selective brain hypothermia (20°C) results in suppressing noxious-evoked movement in canines.