Hideaki Obata

Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain

PurposeTo examine the effect of continuous epidural block initiated before thoracic surgery upon early and long-term postoperative pain.MethodsIn a double-blind study, 70 patients scheduled for thoracic surgery under general anesthesia were assigned randomly to receive continuous epidural block with mepivacaine 1.5% initiated either 20 min before surgical incision (Pre group) or at completion of surgery (Post group). In both groups the initial dose was 4 ml, followed by a continuous infusion at 4 ml·hr−1 until 72 hr after operation. Indomethadn suppositories, 50 mg, were administered on request as supplementary analgesics. Visual analogue scale at rest was assessed four hours after operation, and then every 24 hr after operation on postoperative days 1 through 7, and also days 14 and 30. At three and six months after operation, all patients were interviewed by telephone with respect to postoperative pain. The most severe pain was assessed using modified numerical rating scale.ResultsBy a visual analogue scale, postoperative pain was less in the Pre group than in the Post group at four hours, two and three days after operation (P < 0.05). By a numerical rating scale six months after operation, pain was less in the Pre group than in the Post group (P = 0.015). The percentage of pain-free patients was higher in the Pre group than in the Post group at three (P = 0.035) and six (P = 0.0086) months after operation.ConclusionContinuous epidural block initiated prior to surgery may reduce long-term post-thoracotomy pain.RésuméObjectifExaminer l’effet d’un blocage épidural continu, amorcé avant une intervention chirurgicale thoracique, sur la douleur postopératoire précoce et de long terme.MéthodeLétude à double insu a porté sur 70 patients qui devaient subir une opération thoracique sous anesthésie générale. Répartis au hasard, ils ont reçu un blocage épidural continu avec de la mépivacaïne à 1,5 %, administrée soit 20 min avant l’incision chirurgicale (groupe Pré), soit à la fin de l’intervention (groupe Post). Pour tous, la dose initiale a été de 4 ml suivie d’une perfusion continue à 4 ml·hr−1 jusqu’à 72 h après l’opération. Des suppositoires de 50 mg d’indométhacine ont été administrés sur demande pour compléter l’analgésie. La douleur a été évaluée au repos selon l’échelle visuelle analogique, 4 h après l’opération et puis à toutes les 24 h des jours 1 à 7 et aussi les jours 14 et 30. Trois mois et six mois après l’opération, tous les patients ont été interrogés par téléphone au sujet de la douleur postopératoire. La douleur la plus sévère a été évaluée en utilisant une échelle d’estimation numérique modifiée.RésultatsSelon l’échelle visuelle analogique, la douleur postopératoire était plus faible chez les patients du groupe Pré que chez ceux du groupe Post à 4 h, deux et trois jours après l’opération (P < 0,05). Selon une échelle d’estimation numérique, la douleur était moins intense chez les patients du groupe Pré que chez ceux du groupe Post (P = 0,015) six mois après l’opération. Le pourcentage de patients sans douleur était plus élevé dans le groupe Pré que dans le groupe Post à trois mois (P = 0,035) et à six mois (P = 0,0086) après l’opération.ConclusionLe blocage épidural continu amorcé avant l’intervention chirurgicale peut réduire la douleur qui se prolonge après une thoracotomie.

Gabapentin Acts within the Locus Coeruleus to Alleviate Neuropathic Pain

Background:Gabapentin recruits descending inhibition to produce analgesia after nerve injury, but whether this is a local action in the brainstem is unknown. The authors hypothesized that gabapentin activates noradrenergic neurons in the locus coeruleus (LC) by a local action. Methods:Male rats underwent L5–L6 spinal nerve ligation (SNL) and received drugs by intra-LC or systemic routes for behavior testing, immunohistochemistry in the LC, and microdialysis in the spinal dorsal horn. In other studies, brainstem slices from normal and SNL animals were used for immunohistochemistry. Results:SNL increased phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB)–expressing nuclei bilaterally in the LC, and increased noradrenaline release in the spinal dorsal horn. Gabapentin, whether in isolated brainstem slices or in conscious or anesthetized animals, increased pCREB-expressing nuclei in the LC. The net increase in pCREB expression by gabapentin did not differ between normal and SNL conditions. This gabapentin-induced pCREB activation in LC neurons was abolished by an AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Intra-LC–injected gabapentin reduced hypersensitivity in SNL rats in a dose-dependent manner. Both intra-LC coadministration of CNQX and intrathecal administration of the &agr;2-adrenoceptor antagonist idazoxan blocked antihypersensitivity by intra-LC gabapentin. Intravenous gabapentin induced noradrenaline release in the spinal dorsal horn. The net amount of noradrenaline release by gabapentin is larger in SNL rats compared with the normal condition, although the percentage increases from the baseline were the same. Conclusions:These results suggest that gabapentin acts directly in the brainstem via a glutamate-dependent mechanism to stimulate descending inhibition to produce antihypersensitivity after peripheral nerve injury.

Effects of 5-HT2 and 5-HT3 receptors on the modulation of nociceptive transmission in rat spinal cord according to the formalin test

We used the formalin test to clarify the 5-hydroxytryptamine (5-HT) receptor subtypes involved in the modulation of spinal nociceptive transmission in rats. Intrathecal administration of a 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetraline (8-OH-DPAT; 1, 10, and 30 microg), or a 5-HT1B receptor agonist, 1, 4-dihydro-3-(1, 2, 3, 6-tetrahydro-4-pyridinyl)-5H-pyrrol (3, 2-b) pyridin-5-one (CP 93129; 1 and 10 microg), produced no significant change in the number of flinches. A 5-HT(2) receptor agonist, (+/-)-2, 5-dimethoxy-4-iodoamphetamine (DOI; 10, 30, and 100 microg), and a 5-HT3 receptor agonist, 2-methyl-5-HT (100 and 300 microg), produced dose-dependent decreases in the number of flinches in phases 1 (1 to 6 min) and 2 (10 to 61 min) of the test. The antinociceptive effects of DOI and 2-methyl-5-HT were antagonized by intrathecal pretreatment with a 5-HT2 receptor antagonist, ketanserin, and a 5-HT3 receptor antagonist, 3-tropanyl-3, 5-dichlorobenzoate (MDL-72222), respectively. These results suggest that 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception to chemical stimuli.

The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain.

Antidepressants are often used to treat neuropathic pain. In the present study, we determined the antiallodynic effects of selective monoamine reuptake inhibitors in the spinal cord in a rat model of neuropathic pain. Mechanical allodynia was produced by tight ligation of the left L5 and L6 spinal nerves and determined by applying von Frey filaments to the left hindpaw. A serotonin noradrenaline reuptake inhibitor, milnacipran, a selective serotonin reuptake inhibitor, paroxetine, or a selective noradrenaline reuptake inhibitor, maprotiline, was administered intrathecally via a chronically implanted catheter. Milnacipran produced dose-dependent antiallodynic effects at doses between 3 &mgr;g and 100 &mgr;g. The effect lasted for 7 h after injection of 100 &mgr;g (P < 0.05). The antiallodynic effect of 30 &mgr;g of milnacipran was attenuated by intrathecal coadministration of 30 &mgr;g of yohimbine, an α2-adrenoceptor antagonist, 30 &mgr;g of methysergide, a serotonin receptor antagonist, or 30 &mgr;g of atropine, a muscarinic receptor antagonist (P < 0.01, respectively). Intraperitoneal administration of milnacipran had no antiallodynic effects at doses of 3 to 30 mg/kg. Antiallodynic effects were not produced by intrathecal administration of paroxetine (10 to 100 &mgr;g) or maprotiline (10 to 100 &mgr;g). These findings suggest that simultaneous inhibition of serotonin and noradrenaline reuptake in the spinal cord is essential to mediate antiallodynic effects. Milnacipran might be effective for suppression of neuropathic pain.

Antiallodynic effect of intrathecally administered 5-HT2 agonists in rats with nerve ligation

&NA; We examined the antiallodynic effect of intrathecally administered serotonin receptor agonists including 5‐HT1A, 5‐HT1B, 5‐HT2 and 5‐HT3 receptor subtypes in a rat model using spinal nerve ligation at L5 and L6. Administration of the 5‐HT2 receptor agonist, &agr;‐methyl‐5‐hydroxytryptamine maleate (&agr;‐m‐5‐HT; 3–100 &mgr;g) or (±)‐1‐(4‐iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane hydrochloride (DOI; 10–100 &mgr;g), showed dose‐dependent antiallodynic actions with no associated motor weakness. The antiallodynic action of &agr;‐m‐5‐HT was more potent than that of DOI. The effects of 5‐HT2 agonists on tactile allodynia were reversed by intrathecal pretreatment with the selective 5‐HT2 antagonist ketanserin and with the mixed 5‐HT1 and 5‐HT2 antagonist methysergide. Neither the mixed 5‐HT1A and 5‐HT1B antagonist cyanopindolol nor the selective 5‐HT3 antagonist MDL72222 attenuated antiallodynic effects induced by 5‐HT2 agonists. In contrast, the selective 5‐HT1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin hydrobromide (8‐OH‐DPAT; 1–50 &mgr;g), the 5‐HT1B agonist 5‐methoxy‐3‐(1,2,5,6‐tetrahydro‐4‐pyridinil)‐1H‐indol (RU‐24969; 10–100 &mgr;g) and the 5‐HT3 agonist 2‐methyl‐5‐hydroxytryptamine maleate (2‐m‐5‐HT; 30–300 &mgr;g) all lacked significant antiallodynic action with intrathecal administration. These results indicate that the 5‐HT2 receptor plays an essential role in spinal suppression of neuropathic pain by 5‐HT.

An increase in spinal cord noradrenaline is a major contributor to the antihyperalgesic effect of antidepressants after peripheral nerve injury in the rat.

Summary Increase in noradrenaline in the spinal cord plays an important role in the antihyperalgesic effects of SNRIs and SSRIs in rats with neuropathic pain. ABSTRACT Antidepressants are often used for the treatment of neuropathic pain. Clinical studies suggest that the efficacy of serotonin (5‐HT) and noradrenaline (NA) reuptake inhibitors (SNRIs) for neuropathic pain is greater than that of selective 5‐HT reuptake inhibitors (SSRIs). In the present study, we determined the efficacy and mechanisms involved in the antihyperalgesic effects of milnacipran, an SNRI, compared with paroxetine, an SSRI, and maprotiline, a selective NA reuptake inhibitor, using a rat model of neuropathic pain. Male Sprague‐Dawley rats underwent spinal nerve ligation (SNL), and the withdrawal threshold to paw pressure was measured. Intraperitoneal injection of milnacipran (3–30 mg/kg) produced a dose‐dependent antihyperalgesic effect. The effect was reversed by intrathecal injection of the α2‐adrenoceptor antagonist idazoxan (30 μg), but not by various 5‐HT receptor antagonists. Paroxetine produced an antihyperalgesic effect only at the highest dose tested (10 mg/kg). This effect was reversed by intrathecal injection of both idazoxan and ondansetron (30 μg), a 5‐HT3 receptor antagonist. Maprotiline produced an antihyperalgesic effect (10 and 30 mg/kg), and the effect was reversed by intrathecal idazoxan. In microdialysis studies, NA and 5‐HT concentrations in the spinal dorsal horn were increased after injection of either milnacipran or paroxetine, and only NA was increased after maprotiline. Furthermore, the NA content in the spinal cord of SNL rats was greater than that in normal animals. These findings suggest that an increase in NA in the spinal cord plays an important role in the antihyperalgesic effects of not only NA reuptake inhibitors but also SSRIs.

The comparative effects of propofol versus thiopental on middle cerebral artery blood flow velocity during electroconvulsive therapy.

Electroconvulsive therapy provokes abrupt changes in both systemic and cerebral hemodynamics. An anesthetic that has a minor effect on cerebral hemodynamics might be more suitable for patients with intracranial complications, such as cerebral aneurysm. The purpose of our present study was to compare the effects of thiopental and propofol on cerebral blood flow velocity. We continuously compared cerebral blood flow velocity at the middle cerebral artery (MCA) during electroconvulsive therapy, using propofol (1 mg/kg, n = 20) versus thiopental (2 mg/kg, n = 20) anesthesia. Systemic hemodynamic variables and flow velocity at the MCA were measured until 10 min after the electrical shock. Heart rate and arterial blood pressure increased in the thiopental group until 5 min after the electrical shock. In the propofol group, an increase in mean blood pressure was observed to 1 min after the electrical shock. Mean flow velocity at the MCA decreased after anesthesia in both groups, and increased at 0.5–3 min after the electrical shock in the thiopental group and at 0.5 and 1 min after the shock in the propofol group. The flow velocities at 0.5–5 min after the electrical shock were significantly more rapid in the thiopental group compared with the propofol group. {abs} Implications Cerebral blood flow velocity change, measured by transcranial Doppler sonography during electroconvulsive therapy, was minor using propofol anesthesia compared with barbiturate anesthesia. Propofol anesthesia may be suitable for patients who cannot tolerate abrupt cerebral hemodynamic change.

Peripheral 5-HT2A receptor antagonism attenuates primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury in rats.

Abstract Inflammation or injury of peripheral tissue causes release of chemical mediators, including 5‐hydroxytryptamine (5‐HT), which is involved in the facilitation of nociceptive transmission and the induction of hyperalgesia. The present study examined the effect of a selective 5‐HT2A receptor antagonist, sarpogrelate, on hyperalgesia and allodynia induced by thermal injury in rats. Mild thermal injury to the hindpaw produces thermal hyperalgesia in the injured area (primary thermal hyperalgesia) and mechanical allodynia in sites adjacent to the primary area (secondary mechanical allodynia). Mechanical allodynia was assessed by paw withdrawal thresholds using von Frey filaments, and thermal hyperalgesia was assessed by paw withdrawal latencies upon exposure to a radiant heat source. Intraperitoneal administration (30–100 mg/kg) or local injection (30–300 &mgr;g) of sarpogrelate 10 min prior to thermal injury attenuated secondary mechanical allodynia in a dose‐dependent manner. Intraperitoneal administration (3–100 mg/kg) or local injection (30–300 &mgr;g) of sarpogrelate 10 min prior to thermal injury attenuated primary thermal hyperalgesia in a dose‐dependent manner. Intraplantar injection of sarpogrelate (300 &mgr;g) to the contralateral hindpaw had no effect on primary thermal hyperalgesia or secondary mechanical allodynia in the ipsilateral paw. The tissue concentration of 5‐HT was measured using microdialysis. Concentrations of 5‐HT increased after thermal injury in both primary and secondary areas, and the increase was not attenuated by pretreatment with sarpogrelate (100 mg/kg, i.p.). These data suggest that 5‐HT released in peripheral tissues after thermal injury sensitizes primary afferent neurons and produces mechanical allodynia and thermal hyperalgesia via peripheral 5‐HT2A receptors.

Antiallodynic effects of intrathecally administered 5-HT2C receptor agonists in rats with nerve injury

&NA; Intrathecal administration of serotonin type 2 (5‐HT2) receptor agonists, &agr;‐methyl‐5‐hydroxytryptamine maleate (&agr;‐m‐5‐HT) or (±)‐1‐(4‐iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane hydrochloride (DOI), produces antiallodynic effects in a rat model of neuropathic pain. In the present study, we examined the antiallodynic effects of intrathecally administered agents which are selective for 5‐HT2C receptors. Allodynia was produced by tight ligation of the left L5 and L6 spinal nerves, and was measured by applying von Frey filaments to the left hindpaw. Administration of the 5‐HT2C receptor agonist, 6‐chloro‐2‐(1‐piperazinyl)‐pyrazine (MK212; 3–100 &mgr;g), 1‐(m‐chlorophenyl)‐piperazine (mCPP; 30–300 &mgr;g), or 1‐(m‐trifluoromethylphenyl)‐piperazine (TFMPP; 30–300 &mgr;g), produced antiallodynic effects in a dose‐dependent manner with no associated motor weakness. The ED50 values of MK212, mCPP, and TFMPP were 39.2, 119.9, and 191.9 &mgr;g, respectively. Intrathecal pretreatment with the selective 5‐HT2C receptor antagonist RS‐102221 (30 &mgr;g) diminished the effects of the highest doses of 5‐HT2C receptor agonists. The preferential 5‐HT2A receptor antagonist ketanserin (30 &mgr;g) did not reverse the effects. In contrast to 5‐HT2C receptor agonists, the antiallodynic effects of intrathecally administered &agr;‐m‐5‐HT (30 &mgr;g) and DOI (100 &mgr;g) were reversed by ketanserin, but not by RS‐102221. These results indicate that 5‐HT2C receptors have a role in spinal inhibition of neuropathic pain, and the effects produced by intrathecal administration of 5‐HT2C receptor agonists are mediated by a mechanism different from that of &agr;‐m‐5‐HT or DOI, which seem to produce their effects through 5‐HT2A receptors.

Spinal microglial expression and mechanical hypersensitivity in a postoperative pain model: comparison with a neuropathic pain model.

Background:Postoperative pain control contributes to quality of life. Activation of spinal cord microglia after peripheral nerve injury contributes to mechanical hypersensitivity. The contribution of spinal cord microglia to hypersensitivity after surgery, however, is not well understood. Here, the authors evaluated whether inhibition of spinal microglia reduced postoperative mechanical hypersensitivity, and if so, whether the effect differed from that in a rat neuropathic pain model. Methods:Male Sprague-Dawley rats underwent either unilateral plantar hind paw incision (postoperative pain model) or L5 spinal nerve transection (neuropathic pain model), and the development of mechanical hypersensitivity was assessed using von Frey filaments. The microglial inhibitor minocycline was intraperitoneally administered daily for either 3 or 7 days. Spinal microglial activation was evaluated by OX42 immunohistochemistry. We also tested the effect of intrathecal administration of a p38 mitogen-activated protein kinase inhibitor, SB203580. Results:In the postoperative pain model, minocycline did not suppress mechanical hypersensitivity, but did inhibit an increase in spinal OX42 expression. In contrast, in the neuropathic pain model, minocycline reduced mechanical hypersensitivity in a dose-related manner and inhibited spinal OX42 expression. SB203580 attenuated hypersensitivity in the neuropathic pain model, but not in the postoperative pain model. Conclusions:The results of the present study suggest that spinal OX42 expression has a more important role in the development of neuropathic pain than in postoperative pain, and that an increase in spinal OX42 expression does not contribute to postoperative mechanical hypersensitivity.