Hiroshi Sekiyama

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.

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.

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.

Halothane suppression of spinal sensory neuronal responses to noxious peripheral stimuli is mediated, in part, by both GABAA and glycine receptor systems

Background A major effect of general anesthesia is lack of response in the presence of a noxious stimulus. Anesthetic depression of spinal sensory neuronal responses to noxious stimuli is likely to contribute to that essential general anesthetic action. The authors tested the hypothesis that &ggr;-aminobutyric acid receptor type A (GABAA) and strychnine-sensitive glycine receptor systems mediate halothane depression of spinal sensory neuronal responses to noxious stimuli. Methods Extracellular activity of single spinal dorsal horn wide dynamic range (WDR) neurons was recorded in decerebrate, spinal cord transected rats. Neuronal responses to noxious (thermal and mechanical) and nonnoxious stimuli were examined in the drug-free state. Subsequently, cumulative doses (0.1–2.0 mg/kg) of bicuculline (GABAA antagonist) or strychnine (glycine antagonist) were administered intravenously in the absence or presence of 1 minimum alveolar concentration (MAC) of halothane. Results Halothane, 1.1%, depressed the response of WDR neurons to both forms of noxious stimuli. Antagonists, by themselves, had no effect on noxiously evoked activity. However, bicuculline and strychnine (maximum cumulative dose, 2.0 mg/kg) partially but significantly reversed the halothane depression of noxiously evoked activity. Similar results were seen with most, but not all, forms of nonnoxiously evoked activity. In the absence of halothane, strychnine significantly increased neuronal responses to low threshold receptive field brushing. Conclusion Halothane depression of spinal WDR neuronal responses to noxious and most nonnoxious stimuli is mediated, in part, by GABAA and strychnine-sensitive glycine systems. A spinal source of glycine tonically inhibits some forms of low threshold input to WDR neurons.

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.

Intravenous midazolam suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats.

The effects of intravenously (IV) administered midazolam on noxiously evoked activity of spinal wide dynamic range (WDR) neurons were investigated in decerebrate, spinal-cord-transected cats. Extracellular, single-unit recordings were measured during stimulation by pinching the receptive field on the hind paw and the effect of midazolam at doses of 0.25, 0.5, 1, 2, and 4 mg/kg were measured. Two series of experiments were performed to characterize the analgesic effects of midazolam. In the first, dose-response experiments (n = 59) demonstrated a dose-dependent suppression of the noxiously evoked activity of spinal WDR neurons after midazolam administration. This effect of midazolam was maximal at a dose of 1 mg/kg IV. The second series of experiments (n = 14) demonstrated that a benzodiazepine antagonist, flumazenil (n = 8), promptly reversed the effect of midazolam, while an opioid antagonist, naloxone (n = 6), had no effect on the effect of midazolam. The present study demonstrates that IV administered midazolam suppresses noxiously evoked activity of spinal WDR neurons that is reversible by a benzodiazepine antagonist. This is consistent with an analgesic action of midazolam. (Anesth Analg 1995;80:58-63)

Intravenous infusion of adenosine 5"-triphosphate alleviated a disabling postherpetic neuralgia.

the lateral site of the right leg as well as the dorsal and plantar sites of the right foot. The patient was initially treated at a dermatology clinic with oral valaciclovir (an antiviral agent) and diclofenac (an anti-inflammatory agent), and subsequently, with diclofenac alone for several weeks. Within a month of its onset, the pain in the leg and the dorsum of the foot subsided concomitantly with the skin rash healing. However, severe pain in the plantar site of the foot persisted. Three months after the initial onset, the patient presented at our pain clinic, in a wheelchair, because of intractable pain with severe tactile allodynia on the sole and on the heel of the right foot, which was so severe that it prevented her from walking normally. Resting spontaneous pain was moderate, being rated at 50mm/ 100 mm on the visual analog scale (VAS). However, marked tactile allodynia was observed on the right heel, which was rated at 91/100 mm. Because of the severe touch-evoked allodynia, she could not stand on the right foot, nor could she wear a sock or shoe on the right foot. She could hardly walk, limping and relying mostly on the left foot, stepping on the right tiptoe, and she wore beach sandals. She was treated initially with oral amitriptyline and repeated (caudal) epidural blocks, which resulted in only a slight improvement in her pain status. Five months after the onset of pain, she was admitted to our hospital to study the mechanisms underlying her pain condition, and to seek potentially effective therapeutic measures. After obtaining institutional review board approval and written informed consent from the patient, we assessed various intravenous (IV) drugs for analgesic efficacy. Because the severe tactile allodynia was elicited most prominently when she was trying to walk, she was asked to rate her pain using VAS both at rest (for spontaneous pain) and when standing/stepping (for evoked tactile allodynia) before, during, and after administration of each test drug.

High doses of processed Aconiti tuber inhibit the acute but potentiate the chronic antinociception of morphine.

AIM OF THE STUDY In this study, we investigated the effects of processed Aconiti tuber (PAT), an oriental herbal medicine, at analgesic doses on acute morphine antinociception in morphine-naïve mice and morphine tolerance in morphine-tolerant mice. MATERIALS AND METHODS In acute experiments, mice received subcutaneous (s.c.) morphine (2, 5, or 10 mg/kg) and oral distilled water or PAT (0.3, 1.0, or 3.0 g/kg). The mechanical nociceptive threshold (MNT) and thermal nociceptive latency (TNL) were measured with the tail pressure test and tail flick test, respectively, before, and at 30, 60, 90, and 120 min after s.c. morphine injection. In chronic experiments, mice received s.c. morphine (10 mg/kg) and oral distilled water or PAT (0.3, 1.0, or 3.0 g/kg) once daily for 11 days. MNT was measured before, and at 60 min after, and TNL was measured before, and at 30 min after, daily morphine injections on days 1-11. RESULTS PAT at analgesic doses inhibited the acute antinociceptive effect of morphine dose-dependently in morphine-naïve mice. In contrast, PAT at analgesic doses potentiated the chronic antinociceptive effect of morphine dose-dependently by inhibiting the development of morphine tolerance dose-dependently. These effects of PAT on acute and chronic morphine antinociception were mediated through activation of kappa-opioid receptors. CONCLUSIONS These results indicated that chronic co-administration of PAT at analgesic doses with morphine could provide better-maintained morphine analgesia in a long-term morphine treatment after initial inhibition of acute morphine antinociception for a brief period of time.

Oral Local Anesthesia Successfully Ameliorated Neuropathic Pain in an Upper Limb Suggesting Pain Alleviation through Neural Plasticity within the Central Nervous System: A Case Report.

Neural blockades are considered an alternative to pharmacotherapy for neuropathic pain although these blockades elicit limited effects. We encountered a patient with postbrachial plexus avulsion injury pain, which was refractory to conventional treatments but disappeared temporarily with the administration of the local anesthetic lidocaine around the left mandibular molar tooth during dental treatments. This analgesic effect on neuropathic pain by oral local anesthesia was reproducible. Under conditions of neuropathic pain, cerebral somatotopic reorganization in the sensorimotor cortices of the brain has been observed. Either expansion or shrinkage of the somatotopic representation of a deafferentated body part correlates with the degree of neuropathic pain. In our case, administration of an oral local anesthetic shrank the somatotopic representation of the mouth, which is next to the upper limb representation and thereby expanded the upper limb representation in a normal manner. Consequently, oral local anesthesia improved the pain in the upper limb. This case suggests that pain alleviation through neural plasticity within the brain is related to neural blockade.

Pressure sore as a possible complication of lower central neuraxial blockade

minutes after the first epidural bolus injection, an epidural infusion of plain 1% mepivacaine was started at a rate of 6ml·h 1. Throughout the operation, the patient was in the lithotomy position. To prevent pressure sores, the operating table was covered with silicon jelly pads. The operative area was sterilized with 0.2% chlorhexidine gluconate. Surgery lasted about 4h and 30 min. The patient was in the lithotomy position for 5h. During surgery her systolic blood pressure varied between 90 and 110 mmHg, and her general condition was stable. The bladder temperature did not decrease below 36°C. The total blood loss was 320ml, and we did not give a blood transfusion. At the end of surgery, we checked the condition of the whole body surface of the patient. Although the disinfectant, chlorhexidine gluconate, flowed along her sides a little, there was no change in her sacral skin. Postoperatively, an epidural infusion was started with 0.25% bupivacaine 2ml·h 1 and fentanyl 15 μg·h 1. The patient could move her legs when the continuous epidural infusion was started. She remained hemodynamically stable throughout the first postoperative night. The morning after surgery, 24 hr after the beginning of surgery, a large erythema was discovered on her sacral skin. The erythema was 6 4 cm in size and was tinged with violet (Fig. 1). There were no skin lesions on her body except for the sacral area. The patient did not complain of pain on her sacral skin. A dermatologist confirmed the diagnosis of pressure sore. We informed her about the sacral skin lesion, and she consented to treatment with ointments containing disinfectant and anti-decubitus ulcer drugs. All of the erythema had completely disappeared uneventfully by the fourth postoperative week.