Shigehito Sawamura

Isoflurane and Nociception: Spinal α2A Adrenoceptors Mediate Antinociception while Supraspinal α1 Adrenoceptors Mediate Pronociception

Background The authors recently established that the analgesic actions of the inhalation anesthetic nitrous oxide were mediated by noradrenergic bulbospinal neurons and spinal &agr;2B adrenoceptors. They now determined whether noradrenergic brainstem nuclei and descending spinal pathways are responsible for the antinociceptive actions of the inhalation anesthetic isoflurane, and which &agr; adrenoceptors mediate this effect. Methods After selective lesioning of noradrenergic nuclei by intracerebroventricular application of the mitochondrial toxin saporin coupled to the antibody directed against dopamine &bgr; hydroxylase (D&bgr;H-saporin), the antinociceptive action of isoflurane was determined. Antagonists for the &agr;1 and &agr;2 adrenoceptors were injected at spinal and supraspinal sites in intact and spinally transected rats to identify the noradrenergic pathways mediating isoflurane antinociception. Null mice for each of the three &agr;2-adrenoceptor subtypes (&agr;2A, &agr;2B, and &agr;2C) and their wild-type cohorts were tested for their antinociceptive response to isoflurane. Results Both D&bgr;H-saporin treatment and chronic spinal transection enhanced the antinociceptive effects of isoflurane. The &agr;1-adrenoceptor antagonist prazosin also enhanced isoflurane antinociception at a supraspinal site of action. The &agr;2-adrenoceptor antagonist yohimbine inhibited isoflurane antinociception, and this effect was mediated by spinal &agr;2 adrenoceptors. Null mice for the &agr;2A-adrenoceptor subtype showed a reduced antinociceptive response to isoflurane. Conclusions The authors suggest that, at clinically effective concentrations, isoflurane can modulate nociception via three different mechanisms: (1) a pronociceptive effect requiring descending spinal pathways, brainstem noradrenergic nuclei, and supraspinal &agr;1 adrenoceptors; (2) an antinociceptive effect requiring descending noradrenergic neurons and spinal &agr;2A adrenoceptors; and (3) an antinociceptive effect mediated within the spinal cord for which no role for adrenergic mechanism has been found.

Effect of Methylprednisolone on Neuropathic Pain and Spinal Glial Activation in Rats

Background: Basic data are lacking regarding the efficacy and mechanisms of action of corticosteroids in neuropathic pain. Because recent studies indicate that spinal glial activation mediates the pathologic pain states, the authors sought to determine the effects of systemic and intrathecal methylprednisolone on the development and maintenance of neuropathic pain and spinal glial activation in a rat model. Methods: Rats were anesthetized, and L5 and L6 spinal nerves were tightly ligated. Then, continuous infusion of systemic (4 mg · kg−1 · day−1) or intrathecal (80 μg · kg−1 · day−1) methylprednisolone or saline was started. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively with von Frey and Hargreaves tests, respectively. Spinal astrocytic activation was evaluated with glial fibrillary acidic protein immunoreactivity on day 7. In other groups of rats, continuous 3-day treatment with intrathecal methylprednisolone or saline was started 7 days after spinal nerve ligation, when neuropathic pain had already developed. Behavioral tests and immunostaining were performed up to 3 weeks after the treatment. Results: Spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia on days 4 and 7 postoperatively. Glial fibrillary acidic protein immunoreactivity was remarkably enhanced on day 7. Both systemic and intrathecal methylprednisolone inhibited the development of neuropathic pain states and glial activation. Three-day treatment with intrathecal methylprednisolone reversed existing neuropathic pain state and glial activation up to 3 weeks after the treatment. Conclusion: Systemic and intrathecal methylprednisolone inhibited spinal glial activation and the development and maintenance of a neuropathic pain state in a rat model of spinal nerve ligation.

Glucocorticoid inhibition of neuropathic hyperalgesia and spinal Fos expression.

Glucocorticoids are used to treat patients suffering from neuropathic pain and complex regional pain syndromes (CRPS). Previously we found that once-daily injections of the glucocorticoid methylprednisolone had no antihyperalgesic effect in the rat sciatic nerve transection model for CRPS, but on the basis of CRPS clinical data, we hypothesized that a continuous infusion of methylprednisolone might prove effective. We further postulated that the antihyperalgesic effects of glucocorticoids were mediated by the inhibition of spinal neuron hyperactivity and by the depletion of substance P or its NK(1) receptor. This study tested the effects of continuously infused methylprednisolone in sciatic nerve-transected rats. Continuous infusion of methylprednisolone (3 mg. kg(-1). d(-1) for 21 days), started after the development of neuropathic hyperalgesia, reversed both heat and mechanical hyperalgesia over 2 wk, and this effect persisted for at least 1 wk after discontinuing methylprednisolone. In addition, continuous methylprednisolone infusion partially reversed nerve injury-evoked Fos expression in the dorsal horns, suggesting that glucocorticoids can inhibit the spinal neuron hyperactivity induced by chronic sciatic nerve transection. Finally, no changes were observed in spinal substance P or NK(1) immunoreactivity after chronic methylprednisolone infusion, suggesting that the depletion of this neuropeptide or its receptor does not contribute to the antihyperalgesic actions of glucocorticoids.

Role for cyclooxygenase 2 in the development and maintenance of neuropathic pain and spinal glial activation

Background: Lines of evidence have indicated that cyclooxygenase 2 plays a role in the pathophysiology of neuropathic pain. However, the site and mechanism of its action are still unclear. Spinal glia has also been reported to mediate pathologic pain states. The authors evaluated the effect of continuous intrathecal or systemic cyclooxygenase-2 inhibitor on the development and maintenance of neuropathic pain and glial activation in a spinal nerve ligation model of rats. Methods: Continuous intrathecal infusion of meloxicam (32 or 320 &mgr;g · kg−1 · day−1) or saline was started immediately after L5–L6 spinal nerve ligation. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively. Spinal astrocytic activation was evaluated with glial fibrially acidic protein immunoreactivity on day 7. In other groups of rats, continuous intrathecal meloxicam was started 7 days after spinal nerve ligation, and effects on established neuropathic pain and glial activation were evaluated. Last, effects of continuous systemic meloxicam (16 mg · kg−1 · day−1) on existing neuropathic pain and glial activation were examined. Results: Intrathecal meloxicam prevented the development of mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation. It also inhibited spinal glial activation responses. In contrast, when started 7 days after the nerve ligation, intrathecal meloxicam did not reverse established neuropathic pain and glial activation. Systemic meloxicam started 7 days after ligation partially reversed neuropathic behaviors but not glial activation. Conclusions: Spinal cyclooxygenase 2 mediates the development but not the maintenance of neuropathic pain and glial activation in rats. Peripheral cyclooxygenase 2 plays a part in the maintenance of neuropathic pain.

Corticotropin-releasing factor mediates the antinociceptive action of nitrous oxide in rats.

Background Exposure to nitrous oxide activates brainstem noradrenergic nuclei and descending inhibitory pathways, which produce the acute antinociceptive action of nitrous oxide. Because corticotropin-releasing factor (CRF) can produce activation of noradrenergic neurons in the locus ceruleus, the authors sought to determine whether it might be responsible for the antinociceptive action of nitrous oxide. Methods Male Sprague-Dawley rats (250–300 g) were exposed for 60 min to room air or 25, 50 or 70% nitrous oxide in oxygen. Brain sections including the hypothalamus were immunostained for both c-Fos (a marker of neuronal activation) and CRF and the percentage of CRF-positive neurons expressing c-Fos was determined. The functional consequences of changes in CRF were investigated by assessing the effect of intracerebroventricular administration of a CRF antagonist (&agr;-helical CRF9–41, 20 &mgr;g/10 &mgr;l) on both activation of locus ceruleus noradrenergic neurons and the antinociception (with the tail-flick latency test) produced by nitrous oxide. Results Inhalation of nitrous oxide induced a dose-dependent increase in c-Fos expression in CRF-positive neurons in the paraventricular nucleus of the hypothalamus. Intracerebroventricular administration of CRF antagonist inhibited nitrous oxide-induced c-Fos expression in the locus ceruleus and the antinociceptive effect of nitrous oxide. Conclusions Nitrous oxide activates the CRF system in the brain, which results in stimulation of noradrenergic neurons in the locus ceruleus and its consequent antinociceptive effect.

Anesthesia for Patients with Congenital Insensitivity to Pain and Anhidrosis: A Questionnaire Study in Japan

UNLABELLED We investigated the anesthetic management of patients with congenital insensitivity to pain and anhidrosis (CIPA) in Japan. CIPA is a rare inherited disease characterized by a lack of pain sensation and thermoregulation. Although lacking pain sensation, some patients do have tactile hyperesthesia. Thus, anesthetics are a necessity during operations. We also determined that because patients with CIPA have problems with thermoregulation, temperature management is a concern during the perioperative period and sufficient sedation is necessary to avoid accidental fractures. Additionally, it was found that the use of muscle relaxants does not present a problem, malignant hyperthermia is not associated with CIPA, and that the possibility of abnormalities in the autonomic nervous system must be taken into consideration. Therefore, patients with CIPA can be safely managed with anesthesia. IMPLICATIONS We investigated the anesthetic management of patients with congenital insensitivity to pain and anhidrosis. We clarified the following three important points: anesthesia is necessary, temperature management must be maintained, and there must be sufficient perioperative sedation in the anesthetic management of patients with congenital insensitivity to pain and anhidrosis.

Thoracic epidural catheter insertion using the caudal approach assisted with an electrical nerve stimulator in young children

Objectives We evaluated whether thoracic epidural catheter placement using the caudal approach and assisted with an electrical stimulator could be performed in young children. Methods Ten young children (1-4 years) who underwent abdominal surgeries were studied. Under general anesthesia without muscle relaxants, caudal catheter placement was performed using an 18-gauge Crawford-type needle and a 20-gauge radiopaque epidural catheter with a stainless-steel stylet. A metal adapter and a 3-way stopcock were attached to the catheter to connect to an electrical stimulator and to inject physiological saline. Electrical stimulation was performed intermittently while advancing the catheter until it reached the target length. The catheter position was confirmed on postoperative roentgenogram. Results The mean age of the subjects was 32.2 ± 10.1 months (13-48 months), and the height was 85.3 ± 6.1 cm (72-93 cm). In 9 of 10 patients, an epidural catheter could be placed at the first insertion. In 1 patient, the catheter could be placed successfully at the second insertion. The electrical current required for muscle contraction at the target length was 5.8 ± 1.5 mA. Conclusion Electrical stimulation reliably indicated the location of the catheter tip. This technique for thoracic epidural catheter insertion was easy to perform and could be used in young children.

Opioidergic and adrenergic modulation of formalin-evoked spinal c-fos mRNA expression and nocifensive behavior in the rat

Fos protein expression has been used to reflect neuronal activation in pain processing pathways although analgesics may uncouple behavioral and Fos responses. We determine whether formalin-induced spinal c-fos mRNA expression (Northern blotting) correlates with nocifensive behavior following pretreatment with morphine, the alpha2-adrenoceptor agonist dexmedetomidine, or their respective antagonists naloxone and atipamezole. Both opiate and alpha2-adrenoceptor agonists reduced formalin-induced c-fos gene transcription and nocifensive behavior via their cognate receptors. Unexpectedly, blockade of either the opiate or alpha2-adrenergic receptors, alone, caused an increase in formalin-evoked c-fos mRNA; while blocking the opiate receptor had no effect on formalin-induced behavior, alpha2-adrenoceptor block had an analgesic effect, indicating discordance between c-fos message transcription and nocifensive behavior. We concluded that the formalin-induced spinal c-fos signal was a poor predictor of the behavioral response to pharmacological manipulation of pain processing pathways.

Effects of Topical Application of Clonidine Cream on Pain Behaviors and Spinal Fos Protein Expression in Rat Models of Neuropathic Pain, Postoperative Pain, and Inflammatory Pain

Background:Clonidine can effectively reduce pain and/or hypersensitivity. However, the antihypersensitivity effects of clonidine topically applied in cream (CC) have not been investigated. The authors evaluated effects of topical application of CC on pain behaviors and spinal Fos-like immunoreactivity in rats with hypersensitivity. Methods:Clonidine (30, 100, and 300 &mgr;g/g) was prepared in a cream base. In rat models of neuropathic pain, inflammatory pain, and postoperative pain, the authors evaluated effects of CC (0.1 g), topically applied onto the plantar surface of the injured or uninjured paw, on thermal hyperalgesia and mechanical allodynia to von Frey filaments. The authors also evaluated effects of CC on lumbar spinal Fos-like immunoreactivity. Results:In neuropathic rats, CC applied onto the injured paw reduced thermal hyperalgesia and mechanical allodynia dose dependently, whereas CC applied onto the uninjured paw had no effect. The antihypersensitivity effects of CC were antagonized by intraperitoneal yohimbine (10 mg/kg). Further, CC reduced Fos-like immunoreactivity in neuropathic rats. In contrast, CC in a single dose had no effects on hyperalgesia, allodynia, or Fos-like immunoreactivity in rats with inflammatory or postoperative pain. In rats with postoperative pain, CC repeatedly applied for 6 days reduced thermal hyperalgesia, but not mechanical allodynia, in the postoperative days, whereas it had no effects on hyperalgesia or allodynia in those with inflammatory pain. Conclusions:Topical CC in concentrations examined significantly reduced hypersensitivity and lumbar spinal Fos-like immunoreactivity in rats with neuropathic pain, probably through activation of peripherally located &agr;2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.

Beneficial effects of the prone position on the incidence of barotrauma in oleic acid‐induced lung injury under continuous positive pressure ventilation

Background: Factors that contribute to ventilator‐induced barotrauma are not well defined. This study investigates the effects of posture on ventilator‐induced barotrauma, as well as arterial oxygenation.