Kunie Nakajima

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.

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 nociceptive mechanism of 5-hydroxytryptamine released into the peripheral tissue in acute inflammatory pain in rats

The present study examined the contribution of 5‐hydroxytryptamine (5‐HT) to acute peripheral inflammatory pain in rats. We used formalin test in this study. After formalin injection into the rat hind paw, biphasic pain‐related behavior (phases 1 and 2) was observed. A microdialysis study revealed that 5‐HT was released into the formalin injection site in a formalin concentration‐dependent manner (1.25–5%), and its peak time was 18min after the injection. Previous studies suggest that peripheral 5‐HT2 receptors are involved in inflammatory pain. Therefore, we next examined whether 5‐HT2A and 5‐HT2C receptors are involved, and from where 5‐HT is released in the formalin test. Local pretreatment with a selective 5‐HT2A receptor antagonist, ketanserin, and selective 5‐HT2C receptor antagonists, RS102221 and SB242084, inhibited the number of flinches in early part of phase 2 (phase 2A) of the formalin test in a dose‐dependent manner. Peripheral pretreatment with sodium cromoglycate (cromolyn), a mast cell membrane stabilizer, completely suppressed 5‐HT release and inhibited phase 2 responses of the formalin test. These drugs inhibited c‐fos expression in the superficial layer of the spinal dorsal horn of segments L4‐5 at 2h after formalin injection. These results indicate that 5‐HT released into peripheral tissue and its receptors, 5‐HT2A as well as 5‐HT2C, at the periphery have an important role in pain‐related behaviors during acute peripheral inflammation.

Monoamine-Dependent, Opioid-Independent Antihypersensitivity Effects of Intrathecally Administered Milnacipran, a Serotonin Noradrenaline Reuptake Inhibitor, in a Postoperative Pain Model in Rats

The neurotransmitters serotonin (5-HT) and noradrenaline (NA) have important roles in suppressing nociceptive transmission in the spinal cord. In the present study, we determined the efficacy and nature of the antihypersensitivity effects of milnacipran, a 5-HT and NA reuptake inhibitor (SNRI), in the spinal cord in a rat model of postoperative pain. Sprague-Dawley rats were used in all experiments. An incision was made on the plantar aspect of the hind paw. Mechanical hypersensitivity was measured by determining the withdrawal threshold to von Frey filaments applied to the paw. Drugs were administered intrathecally 24 h after paw incision. Microdialysis studies of the dorsal horn of the lumbar spinal cord were also performed to measure 5-HT and NA levels after systemic injection of milnacipran. Milnacipran (1–30 μg) produced dose-dependent antihypersensitivity effects. The effect lasted 6 h after the 30-μg injection. Doses of 30 μg or less produced no abnormal behavior. The peak antihypersensitivity effect of 10 μg of milnacipran was blocked by intrathecal pretreatment with antagonists of the α2-adrenoceptor (idazoxan; 30 μg) or 5-HT receptors (methysergide; 30 μg). Intrathecal pretreatment with 30 μg of naloxone, a μ-opioid receptor antagonist, did not reverse the effect of milnacipran. Isobolographic analysis indicated antinociceptive synergism between milnacipran and morphine. Microdialysis studies revealed that milnacipran increased both 5-HT and NA levels in the spinal dorsal horn. These findings suggest that the antihypersensitivity effect of intrathecal milnacipran in the postoperative pain model is monoamine-mediated. Combined administration of an SNRI with morphine might be a promising treatment to suppress postoperative hypersensitivity.

Lack of analgesic efficacy of spinal ondansetron on thermal and mechanical hypersensitivity following spinal nerve ligation in the rat.

The balance between descending inhibition and facilitation is thought to be disturbed in chronic pain states. Increased facilitation by spinally released serotonin has been suggested by demonstration that mechanically evoked neuronal responses of wide dynamic range neurons are inhibited by 5-HT3 receptor antagonists in rats following spinal nerve ligation (SNL) but not sham operation. Despite these physiologic data, the effects of spinal 5-HT3 receptor blockade on behavioral hypersensitivity and neurochemical alterations in spinal serotonergic system have not been thoroughly investigated following spinal nerve ligation in the rat. To test this, we acutely injected intrathecal ondansetron in rats between 14 and 30 days after SNL and assessed effects on thermal and mechanical hypersensitivity. We also determined the density of serotonergic nerve fibers, serotonin content and the levels of 5-HT3 receptors within the spinal cord at this time point. Intrathecal ondansetron (1, 3, 10, 30, and 100microg) produced no effect on behavioral measures of thermal or mechanical hypersensitivity whereas intrathecal morphine (1microg) and gabapentin (200microg) partially reversed thermal and mechanical hypersensitivity following SNL. In addition, SNL did not alter the density of serotonergic fibers or 5-HT3 receptor immunoreactivity or spinal tissue content of 5-HT within the dorsal horn. These results do not support anatomic plasticity of descending serotonergic pathways or tonic 5-HT3 receptor activity in maintaining hypersensitivity after nerve injury and in contrast to previous studies fail to demonstrate an anti-hypersensitivity effect of intrathecal injection of the 5-HT3 receptor antagonist ondansetron. Importantly, behavioral measures of mechanical hypersensitivity assess threshold responses whereas physiological studies of mechanically evoked neuronal responses involve application of suprathreshold stimuli. Thus, suprathreshold or more intense stimuli may be necessary to recruit descending serotonergic facilitatory drive required to observe the inhibitory effects of ondansetron on spinal neuronal excitability and behavioral hypersensitivity.

The Antihyperalgesic Effects of Intrathecal Bupropion, a Dopamine and Noradrenaline Reuptake Inhibitor, in a Rat Model of Neuropathic Pain

BACKGROUND:Antidepressants are often used for the treatment of neuropathic pain, and their analgesic effects rely on increased noradrenaline and serotonin levels in the spinal cord. Clinical studies have also shown that bupropion, a dopamine and noradrenaline reuptake inhibitor, has strong efficacy in neuropathic pain; however, the role of spinal cord dopamine in neuropathic pain is unknown. We hypothesized that bupropion inhibits neuropathic pain by increasing noradrenaline and dopamine in the spinal cord. In the present study, we determined the efficacy and underlying mechanisms of intrathecal administration of bupropion in a rat model of neuropathic pain. METHODS:Male Sprague-Dawley rats were anesthetized, and right L5 spinal nerve ligation (SNL) was performed to produce mechanical hyperalgesia of the hindpaw. Withdrawal threshold to a paw pressure test was measured before and after intrathecal administration of bupropion, without or with intrathecal antagonists for &agr;2-adrenoceptors and dopamine D2 receptors. In vivo microdialysis was performed in the dorsal horn of the lumbar spinal cord to measure noradrenaline and dopamine concentrations after intrathecal injection of bupropion. We also measured the noradrenaline and dopamine contents in the ipsilateral dorsal lumbar spinal cord in normal rats and in rats 2, 3, and 4 weeks after SNL. RESULTS:Intrathecal injection of bupropion produced a dose-dependent antihyperalgesic effect (3, 10, 30, and 100 &mgr;g, P < 0.001). The effect (30 &mgr;g) was dose-dependently reversed by intrathecal pretreatment (15 minutes before bupropion injection) with the &agr;2-adrenoceptor antagonist idazoxan (3, 10, and 30 &mgr;g, P < 0.001) and D2 receptor antagonist sulpiride (3, 10, and 30 &mgr;g, P < 0.001). Microdialysis revealed that noradrenaline and dopamine concentrations in the spinal dorsal horn were increased after intrathecal injection of bupropion (30 &mgr;g, P < 0.001 and P = 0.001, respectively). Furthermore, the noradrenaline and dopamine contents in the spinal dorsal horn were increased 2 weeks after SNL (P < 0.001 and P = 0.044, respectively) and then decreased gradually. CONCLUSIONS:These findings suggest that plasticity of descending inhibitory pathways such as the noradrenaline and dopamine systems contributes to the maintenance of neuropathic pain and that spinal cord noradrenaline and dopamine both play an inhibitory role in neuropathic pain.

CT-guided nerve block: a review of the features of CT fluoroscopic guidance for nerve blocks

Nerve blocks are an attractive interventional therapy in pain medicine. Several image guidance methods are available to secure the safety, accuracy, and selectivity of the nerve block. Computed tomography (CT) guidance provides a clear view of the vital viscera and vessels that should be avoided by the needle, and accurate placement of the needle tip before neuro-destructive procedures. A recent advance in CT technology is multi-slice CT fluoroscopy, which allows for rapid and easy correction of needle tip placement during insertion. To reduce the radiation dose for both patients and staff, the lowest radiation setting, intermittent quick-check fluoroscopy, and shortening of the planning scan should be used. Preliminary CT scanning with excellent spatial resolution may facilitate the application of CT fluoroscopic guidance to various types of nerve blocks. Here we review celiac plexus and splanchnic nerve blocks, trigeminal nerve block, neurolytic sympathectomy, and spinal intervention performed under CT guidance. Additional large-scale studies are needed to optimize the use of image guidance, especially CT fluoroscopy guidance, for nerve blocks.

Location of major vessels in prone-positioned patients undergoing percutaneous lumbar sympathectomy

IntroductionThe topographic relationship between major vessels and the sympathectomy target is not identical across patients and may not be clear, especially in patients in the prone position. The aim of this study was to provide anatomic data regarding the location of the major vessels (i.e., vena cava and aorta) based on computed tomography (CT) images obtained during lumbar sympathectomy under CT fluoroscopic guidance.MethodsThirty-six patients with peripheral arterial occlusive disease or chronic pain syndrome were treated using fluoroscopic CT-guided percutaneous lumbar sympathectomy between April 2006 and March 2010. We analyzed the shortest distances between the sympathectomy target and the major vessels, and the relationship between the location of the major vessels and the vertebral anterior line using CT images obtained during the procedure.ResultsAt the L3 level, the shortest distances from the right side target to the inferior vena cava were significantly shorter than the other distances (P < 0.05). In 11 of 36 patients (30.6%), the IVC was located dorsal to the vertebral anterior line at the L3 level.ConclusionNeedle insertion for right side sympathectomy at the L3 level may present a higher risk of major vessel puncture than sympathectomy at other sites. CT guidance is recommended for lumbar sympathectomy to reduce the risk of vascular puncture.

Radiofrequency thermocoagulation of the thoracic nerve root guided by high-speed real-time computed tomography fluoroscopy.

lem exists in my own hospital where we are conducting a study into anaesthetic technique but recruitment is slow and those who are included tend to be the fitter patients. On a personal level, I do favour neuroaxial anaesthesia for these patients. All must be positioned carefully but once the block is established, I find that almost every patient goes to sleep without any sedation. All anaesthetists will develop techniques over their careers to treat older patients sympathetically. I think that all in the Working Party would agree that it is best to stick to what you are best at, but to be careful of any drug that may impair cognitive function. I agree with Dr Plumb that oxygen should be prescribed and would also add that oxygen may be a very simple method of reducing delirium in the hip fracture population [4]. In response to Pawa et al. and to Funnell, one aspect of analgesia that a nerve block provides is ‘dynamic analgesia’. This concept was introduced by Foss et al. [5], in an excellent paper describing fascia iliaca block for hip fracture. In that study, the blocks were inserted in the emergency department, but surgery was performed soon after admission. All sedative drugs should be given with caution in this patient population and we agree that nerve blocks are one technique that can reduce their use.

Changes in Cerebral Oxygenation Assessed by Near-infrared Spectroscopy during Shoulder Arthroscopy in the Beach Chair Position after Brachial Plexus Block

Background: It is well known that patients undergoing shoulder surgery in the Beach Chair Position (BCP) have a potential risk for cerebral ischemia. Using Near-Infrared Spectroscopy (NIRS), this study aimed to test whether cerebral oxygenation in these patients was impaired by brachial plexus block accompanied with general anesthesia. Methods: Ultrasound-guided interscalene brachial plexus block was performed in 26 patients undergoing elective arthroscopic shoulder surgery under general anesthesia. In all subjects, cerebral oxygenation during anesthesia was evaluated by measuring the Tissue Oxygenation Index (TOI) with NIRS. Results: No differences were seen in TOI values between Pre-BCP and Post-BCP periods in both block and non-block sides, despite a decrease in mean blood pressure (P<0.05, repeated measures one-way ANOVA by the Bonferroni post hoc test). Additionally, no differences were seen in TOI values between block and non-block sides at any time point. Conclusion: Changing from the supine position to the BCP did not appear to impair cerebral oxygenation, regardless of brachial plexus block, in patients undergoing shoulder arthroscopy under general anesthesia.