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Loss of peripheral morphine analgesia contributes to the reduced effectiveness of systemic morphine in neuropathic pain.

It is well known that the analgesic potency of morphine is reduced in neuropathic pain. In this study, we demonstrate that the decreased effectiveness of systemic morphine in neuropathic pain might be caused by the loss of morphine analgesia at the periphery. When given s.c. or i.t., the dose-response curves for morphine analgesia in Hargreaves thermal test were shifted rightward in partial sciatic nerve-injured mice compared with control sham-operated mice. The dose-response curves for i.c.v. morphine analgesia, however, were unchanged in nerve-injured mice, indicating no decrease in morphine potency at the supraspinal level. On the other hand, the dose-dependent analgesia produced by intraplantar (i.pl.) morphine in sham-operated mice almost completely disappeared in nerve-injured mice. With the more sensitive algogenic-induced nociceptive flexion test, significant reduction in the analgesic potency of systemic morphine was observed for bradykinin (BK) nociception in nerve-injured mice, and the analgesic effect of i.pl. morphine against BK nociception in sham-operated mice disappeared in nerve-injured mice. In immunohistochemical experiments, we found that, under normal state, mu-opioid receptors (MOPs) were mainly expressed in small-diameter unmyelinated dorsal root ganglion (DRG) neurons and colocalized with bradykinin B2 receptors. When we examined MOP expression in the DRG of nerve-injured mice, we observed a drastic decrease in MOP expression. Altogether, these data suggest that the lower potency of systemic morphine in neuropathic pain could be at least partly caused by the decreased MOP expression in DRG and subsequent loss of peripheral morphine analgesia in such a condition.

Analgesia↗

Two cases of cauda equina syndrome following spinal-epidural anesthesia.

BACKGROUND AND OBJECTIVES: Cauda equina syndrome (CES) is a well-known complication of spinal and epidural anesthesia. Previous reports have implicated lidocaine, chloroprocaine, and procaine in its etiology, but not bupivacaine. METHODS: A 63-year-old man underwent transurethral resection of the prostrate for which he received bupivacaine with glucose intrathecally. Postoperative, he had difficulty in urination and defecation, and magnetic resonance imaging revealed spinal stenosis at the L1-L2 level. The second patient was a 70-year-old woman who underwent hip replacement surgery using a combined spinal-epidural technique. Postoperative, after 42 hours, when the epidural infusion of bupivacaine was stopped, the patient had difficulty in urination and defecation. No anatomical abnormality was found on magnetic resonance imaging. RESULTS: The two patients developed cauda equina syndrome following bupivacaine with glucose injected spinally, and bupivacaine without glucose injected in a combined spinal-epidural technique. CONCLUSIONS: This case report describes two cases of CES following the use of bupivacaine. The first patient had spinal stenosis which could explain this complication; however the explanation for CES in the second patient is uncertain and consequently speculative. We have discussed the possible contributing factors but believe that the etiology of CES in the second patient remains unknown.

Aged↗

Magnesium sulfate treatment in experimental spinal cord injury: emphasis on vascular changes and early clinical results.

Injury to the spinal cord results in disruption of neurons, cell membranes, axons, myelin, and endothelial cells. The aim of this study was to demonstrate the protective effect of magnesium sulfate on the blood-spinal cord barrier after acute spinal cord injury (SCI). This experiment was conducted in two parts. In the first, rats were injected intravenously with Evans blue 2 h after SCI. The laminectomy-only group had no trauma. Contusion injury (50 g-cm) was applied to the trauma and treatment groups. Magnesium sulfate (600 mg/kg) was given to the treatment group immediately after injury. For the second part, clinical evaluations were performed 24 h post surgery. Then, following Evans blue injection, spinal cord samples were obtained from the laminectomy-only, trauma, and treatment groups. For the control group, nontraumatized spinal cord samples were taken after Evans blue injection following clinical examination. Laminectomy did not affect the spinal cord Evans blue content in 2-h and 24-h groups. The trauma increased tissue Evans blue content, and 24-h samples showed more remarkable tissue Evans blue content, suggesting secondary injury. Application of 600 mg/kg of magnesium resulted in lower Evans blue content in the spinal cord than with injury. Remarkable clinical neuroprotection was observed in the treatment groups. Magnesium sulfate showed vaso- and neuroprotective properties after contusion injury to the rat spinal cord. The authors also demonstrated secondary injury of the blood-spinal cord barrier with the Evans blue clearance technique for the first time.

Animals↗

Opioid-related side-effects after intrathecal morphine: a prospective, randomized, double-blind dose-response study.

BACKGROUND AND OBJECTIVE: The aim of this prospective, randomized, double-blind investigation was to assess the dose-effect characteristics of postoperative nausea and vomiting after intrathecal administration of small doses of morphine (from 0.015 to 0.25 mg) in opioid-naïve, non-surgical patients. METHODS: With Ethic Committee approval and written informed consent 144 opioid-naïve patients suffering from non-cancerous chronic back-pain, and receiving intrathecal morphine as diagnostic test for their chronic pain, were randomly allocated to receive intrathecal injection of 0.015 mg (Group I, n=25), 0.03 mg (Group II, n=30), 0.06 mg (Group III, n=31) or 0.25 mg (Group IV, n=33) morphine. The control group consisted in 25 further patients not included in the dose-effect study and receiving a placebo injection of normal saline in the interspinous ligament. A blinded observer recorded the occurrence of pruritus, nausea, vomiting, urinary retention and respiratory depression (respiratory rate<6 bpm) at 2, 4 and 24 h after injection. RESULTS: Clinically significant pain relief was observed in all patients receiving intrathecal morphine but only six patients (25%) of the control group (P=0.0005). The incidence of pruritus was lower in patients of Groups III (6%) and IV (3%) than in Groups I (12%) and II (20%) (P=0.002). The incidence of nausea and vomiting was higher at 2- and 4-h observation times, and decreased 24 h after intrathecal injection. Surprisingly, nausea was more frequent in Groups I (56%) and II (50%) than in Groups III (33%) and IV (24%) (P=0.0005). Vomiting was higher in patients receiving morphine than in control group, but without differences among the four doses. No urinary retention was observed in the control group, while 2 h after intrathecal injection urinary retention was observed in 20-40% of cases, and decreased to less than 10% 24 h after spinal injection without differences among the four doses. CONCLUSIONS: The onset and incidence of minor opioid-related side-effects after intrathecal morphine administration do not depend on its dose, occurring with even very small doses of morphine. Accordingly, they can be considered as a patient-dependent effect of the drug, suggesting the presence of a primary dose-independent excitatory component that might be related to the theory of the bimodal activation of opioid receptors. The very low incidence major respiratory depression prevents us from drawing any conclusion about the dose-effect relationship for this side-effect, and further properly powered studies should be advocated to evaluate major respiratory depression after spinal morphine.

Aged↗

Do propriospinal projections contribute to hindlimb recovery when all long tracts are cut in neonatal or weanling rats?

Lateral hemisection lesions separated by 1 to 3 spinal segments were made on opposite sides of the mithoracic spinal cord in 1-month-old (N = 15; weanling operates) and newborn albino rats (N = 16; neonatal operates). Hindlimb behavior was assessed between 1 and 6 months p.o. for both groups of operates using a protocol and rating system that have previously proved effective in differentiating behavioral recovery of the hindlimbs as a function of age of spinal transection. In addition, at the conclusion of behavioral testing, operates received spinal injections of [3H]proline and HRP caudal to the spinal lesions to determine if lesions were complete and if neurons within the region between the two lesions (interlesion zone) projected into the caudal spinal cord. In both groups of operates, neurons were retrogradely labeled within the interlesion zone bilaterally, primarily in laminae VII-VIII. When both lesions were complete lateral hemisections in weanling operates, little behavioral recovery was observed, similar to complete spinal cord transection (N = 3). However, much greater behavioral recovery was seen, including supporting reactions and locomotor responses, when one or both lesions spared axons along the ventrolateral rim of the white matter. Neurons were retrogradely labeled in the brain stem reticular formation (N = 12) in these cases. All lesions were complete lateral hemisections in neonatal operates but much greater behavioral recovery was seen than in weanling operates with the same lesions, including supporting, placing, and locomotor responses. In an additional group of eight neonatal operates, the spinal cord rostral to the spinal hemisections was transected at 1 month of age. Supportive, placing, and locomotor responses were seen immediately after recovery from anesthesia and responses returned to pretransection levels in six of eight operates over the 10-day survival period. Fink-Heimer impregnation showed that degeneration argyrophilia from the transection bilaterally filled the interlesion zone but little argyrophilia was seen caudal to this region. Our results indicate that an intact propriospinal circuit remains in both neonatal and weanling operates but does not appear to contribute to hindlimb response development or recovery. The greater behavioral recovery in neonatal operates appears due to intrinsic connections (doral root, interneuronal) continuing to be able to drive the spinal circuitry underlying the spared behaviors.

Aging↗

Incidence of intravascular penetration in transforaminal lumbosacral epidural steroid injections.

STUDY DESIGN: A prospective, observational, human, in vivo study. OBJECTIVES: To evaluate the incidence of vascular penetration during fluoroscopically guided, contrast-enhanced, transforaminal lumbar epidural steroid injections (ESIs) and determine whether a "flash" (blood in the needle hub) or aspiration of blood can be used to predict a vascular injection. SUMMARY OF BACKGROUND DATA: Incorrectly placed, intravascular lumbosacral spinal injections result in systemic medication flow that misses the desired target. No previous studies evaluate the incidence of vascular injections in transforaminal ESIs, nor the ability of flash to predict a vascular injection. METHODS: The incidence of flash or positive blood aspiration and the incidence of fluoroscopically confirmed vascular spread were prospectively observed in 670 patients treated with lumbosacral fluoroscopically guided transforaminal ESIs. Presence of a flash or positive aspiration was documented. Contrast was injected to determine whether the needle tip was intravascular. RESULTS: Seven hundred sixty-one transforaminal ESIs were included. The overall rate of intravascular injections was 11.2%. There was a statistically significant higher rate of intravascular injections (21.3%) noted with transforaminal ESIs performed at S1 (n = 178), compared with those at the lumbar levels (8.1%, n = 583). Using flash or positive blood aspirate to predict intravascular injections was 97.9% specific, but only 44.7% sensitive. CONCLUSIONS: There is a high incidence of intravascular injections in transforaminal ESIs that is significantly increased at S1. Using a flash or blood aspiration to predict an intravascular injection is not sensitive, and therefore a negative flash or aspiration is not reliable. Fluoroscopically guided procedures without contrast confirmation are instilling medications intravascularly and therefore not into the desired epidural location. This finding confirms the need for not only fluoroscopic guidance but also contrast injection instillation in lumbosacral transforaminal ESIs.

Adolescent↗

Incidence of intravascular penetration in transforaminal cervical epidural steroid injections.

STUDY DESIGN A prospective, observational, human, study was conducted. OBJECTIVES To evaluate the incidence of vascular penetration during fluoroscopically guided, contrast-enhanced transforaminal cervical epidural steroid injections, and to determine whether the observation of blood in the needle hub can be used to predict a vascular injection. SUMMARY OF BACKGROUND DATA Incorrectly placed intravascular cervical spinal injections result in medication flow systemically and not to the desired target. A recently published study demonstrates a high incidence of intravascular injections in transforaminal lumbosacral epidural injections. No studies so far have evaluated the incidence of vascular injections in transforaminal cervical epidural steroid injections, nor have they calculated the ability of observed blood in the needle hub to predict a vascular injection in the cervical spine.METHODS The incidence of fluoroscopically confirmed intravascular uptake of contrast was prospectively observed in 337 patients treated with cervical transforaminal epidural steroid injections. The ability of observed blood in the needle hub to predict intravascular injection was also investigated. For each subject, the injection level was chosen on the basis of the clinical scenario including history, physical examination, and review of imaging studies. Some patients had multilevel injections. Using fluoroscopic guidance, the authors placed a 25-gauge needle into the epidural space using a transforaminal approach according to accepted standard technique. Needle tip location was confirmed with biplanar imaging. The presence or absence of blood in the needle hub spontaneously ("flash") and after attempted aspiration by pulling back on the syringe's plunger was documented. Contrast then was injected under real-time fluoroscopy to determine whether the location of the needle tip was intravascular. The results were recorded in a prospective manner indicating the presence or absence of blood in the needle hub and whether a vascular pattern was noted with contrast injection, and these were correlated. Relevant epidemiologic data also were recorded. RESULTS The study included 504 transforaminal epidural steroid injections. The overall rate of fluoroscopically confirmed intravascular contrast injections was 19.4%. Use of observed blood in the needle hub to predict intravascular injections was 97% specific, but only 45.9% sensitive. There was no significant difference in intravascular rates related to age or gender. CONCLUSIONS As compared with a previous study of lumbosacral epidural steroid injections, there is an overall higher incidence of intravascular injections with cervical transforaminal epidural steroid injections. Use of observed blood in the needle hub to predict an intravascular injection is not sensitive, and therefore the absence of blood in the needle hub despite aspiration is not reliable. The reported sensitivity and specificity rates are similar to lumbar data. Fluoroscopically guided procedures without contrast confirmation instill medications intravascularly, and therefore not in the desired epidural location. This study confirms that there is a need not only for fluoroscopic guidance, but also for contrast instillation in cervical transforaminal epidural steroid injections.

Adult↗

A nonsurgical approach to low back pain.

Low back pain, a leading cause of disability in the United States, has a significant economic impact not only on lost productivity but also on healthcare expenditures. Approximately a fifth of patients will see multiple physicians in their quest for relief of low back pain. Primary care physicians therefore play a crucial role in the initial approach to these patients. A thorough history and physical examination directed toward the neurologic, orthopedic, and osteopathic evaluation are essential. This article reviews the diagnosis and assessment of pain levels and a triad system of therapy involving cortical, spinal, and peripheral levels. Options include antidepressants, neuroleptics, neurostimulants, and osteopathic manipulative treatment (OMT) (cortical level); opiates, tramadol hydrochloride, and transcutaneous electrical nerve stimulators (spinal level); and nonsteroidal anti-inflammatory drugs, epidural injections, spinal blocks, antispasmodics, physical therapy, muscle relaxants, exercise, and OMT (peripheral level), By choosing a modality directed at each level, the clinician may provide the patient with a pain management program that will maximize the chosen mode of therapy and restore function and mobility.

Analgesics↗

Total spinal anesthesia during combined general-epidural anesthesia in a 7-year-old child.

Total spinal anesthesia (TSA) is a rare complication of lumbar epidural anesthesia through inadvertent spinal injection of local anesthetics following an undiagnosed dural breach or spinal placement of the catheter. TSA has rarely been reported in children. TSA occurred during epidural anesthesia in a 7-year-old child undergoing abdominal surgery. Recent previous lumbar punctures and intrathecal chemotherapy for Burkitt's lymphoma at the same level may have facilitated dural breach. Epidural anesthesia should not be attempted at the same intervertebral level as prior recent lumbar punctures.

Abdomen↗

Effects of ultrasound and diclofenac phonophoresis on inflammatory pain relief: suppression of inducible nitric oxide synthase in arthritic rats.

BACKGROUND AND PURPOSE: The direct effects of ultrasound (US) and phonophoresis of a nonsteroidal anti-inflammatory drug (NSAID) on injured peripheral tissue have been widely investigated, but evidence concerning the effects of central spinal nociceptive modulation seems to be lacking. The purpose of this study was to investigate the peripheral influences of US and phonophoresis on the modulation of spinal inducible nitric oxide synthase (iNOS) expression elicited by hind paw stimulation with an ankle injection of complete Freund adjuvant (CFA). SUBJECTS AND METHODS: Inflammatory arthritis was induced in 18 male Wistar rats with intra-articular tibiotarsal injections of CFA. Serial changes in inflammatory pain reactions, including hind-limb edema, and the locomotor activity of the arthritic animals were measured. Arthritic rats underwent US (n=6), diclofenac phonophoresis (n=6), or sham treatment (n=6) on the CFA-injected leg at 18 hours after injection. At 20 hours after injection, spinal inducible nitric oxide synthase-like immunoreactive (iNOS-LI) cells were examined. RESULTS: Following the CFA injection, all animals' paw diameters and ankle circumferences ipsilateral to the injected leg were significantly increased compared with the values prior to injection. The rearing behavior of arthritic animals had improved significantly after US and diclofenac phonophoresis treatments. The mean total number (+/-SD) of iNOS-LI cells per section of segments L1 and L2 of the bilateral spinal cord of the sham treatment, US, and phonophoresis groups were 531.20+/-6.11, 124.20+/-4.09, and 114.80+/-3.23, respectively. The total numbers of iNOS-LI cells in rats treated with US and diclofenac phonophoresis were significantly smaller than in those receiving sham treatment. There were no significant differences in the total number of iNOS-LI cells ipsilateral to the injected leg between the US and diclofenac phonophoresis groups. DISCUSSION AND CONCLUSION: Ultrasound and phonophoresis treatments probably modulate and prevent the CFA-insult-induced increase in total and regional iNOS-LI neurons. Peripheral use of diclofenac phonophoresis offers little advantage over US alone in affecting the central mechanisms of nociception. The peripheral influences of US and phonophoresis on the central modulation of the spinal nociceptive processing system are important and may reflect the work being done through the neuroplasticity of spinal cord in response to peripheral input of US and phonophoresis.

Adjuvants, Immunologic↗

Trajectory of redirected corticospinal axons after unilateral lesion of the sensorimotor cortex in neonatal rat; a phaseolus vulgaris-leucoagglutinin (PHA-L) tracing study.

The corticospinal neurons of the rat project almost exclusively to the contralateral spinal cord. Retrograde and anterograde tracing experiments showed that only about 2-4% of the corticospinal neurons of the sensorimotor cortex project to the ipsilateral spinal cord in the normal rat. The large majority of corticospinal axons (more than 90%) travel at spinal level at the base of the contralateral dorsal funiculus; in addition a few axons run in the contralateral lateral funiculus and at the base of the dorsal horn. The undecussated axons run in the ipsilateral dorsal (about 1-2%) and ventral (about 1-2%) funiculi. The rearrangement of the corticospinal projections was studied with various tracing methods in rats subjected to unilateral lesion of the sensorimotor cortex at Postnatal Day 2 to 4. Spinal injections of the tracer WGA-HRP that were restricted to the side opposite to the cortical lesion showed a significant increase of retrogradely labeled corticospinal neurons in the intact cortex as compared to the proportion of ipsilateral projections in control experiments. This was consistent with an increased density of anterogradely labeled corticospinal terminals in the spinal cord ipsilateral to an injection of WGA-HRP in the motor cortex opposite to neonatal lesion, in comparison to normal rats. The trajectory of these "aberrant" ipsilateral corticospinal projections resulting from the neonatal lesion of the opposite sensorimotor cortex was analyzed by means of the anterograde tracer phaseolus vulgaris-leucoagglutinin (PHA-L), injected in the motor cortex. These data indicated that decussated corticospinal axons recross at spinal levels, close to their terminal zone, where they appear to ramify and terminate in the spinal gray including the motoneurons. Such recrossing axons thus represent one new possible mechanism, among other previously reported ones, contributing to the increase of ipsilateral corticospinal projections in rats subjected to neonatal cortical lesion.

Animals↗

Spinal anesthesia using single injection small-dose bupivacaine versus continuous catheter injection techniques for surgical repair of hip fracture in elderly patients.

Aging and disease may make elderly patients particularly susceptible to hypotension during spinal anesthesia. We compared the hemodynamic effect of continuous spinal anesthesia (CSA) and small dose single injection spinal anesthesia (SA) regarding the incidence of hypotension. Seventy-four patients aged >75 yr undergoing surgical repair of hip fracture were randomized into 2 groups of 37 patients each. Group CSA received a continuous spinal anesthetic with a titration of 2.5 mg boluses every 15 min of isobaric bupivacaine, while group SA received a single injection spinal anesthetic with 7.5 mg of isobaric bupivacaine. The overall variations in noninvasive automated arterial blood pressure were not statistically significantly different in the 2 groups at baseline and after CSA or SA (not significant). In the SA group, 68% of patients experienced at least one episode of hypotension (decrease in systolic arterial blood pressure greater than 20% of baseline value) versus 31% of patients in the CSA group (P = 0.005). In the SA group, 51% of patients experienced at least one episode of severe hypotension (decrease in systolic arterial blood pressure more than 30% of baseline value) versus 8% of patients in the CSA group (P < 0.0001). In the CSA group, 4.5 +/- 2 mg of ephedrine was injected versus 11 +/- 2 mg in the SA group (P = 0.005). In the CSA group, 5 mg (2.5-10) of anesthetic solution was required versus 7.5 mg in the SA group (P < 0.0001). We conclude that, in elderly patients undergoing hip fracture repair, CSA provides fewer episodes of hypotension and severe hypotension compared with a single intrathecal injection of 7.5 mg bupivacaine.

Aged↗

Caesarean section in a patient with cystic fibrosis.

Severely impaired pulmonary function due to cystic fibrosis is associated with a poor pregnancy outcome. A 19-year-old primigravida with cystic fibrosis had a forced expiratory volume in one second 34% of predicted and a low body mass index of 17.1 kg/m(2) before pregnancy. During pregnancy she required several admissions to hospital for deteriorating pulmonary function due to infection. She also developed gestational diabetes and required overnight feeding via a gastrostomy tube throughout pregnancy to improve her nutritional status. With close medical attention, pulmonary function tests remained stable. A joint decision was made to deliver the baby by caesarean section at 33 weeks' gestation as this was considered optimal time for mother and baby and to avoid potential catastrophic pulmonary deterioration later in pregnancy. A combined spinal-epidural technique provided adequate anaesthesia. Pulmonary function tests were performed in theatre before and after the spinal injection, as well as two and five hours postoperatively. Despite a spinal anaesthetic block to T5 bilaterally, lung function tests remained stable. An epidural infusion provided good postoperative analgesia. The outcome was successful for mother and fetus.

Adult↗

Sectional neuroanatomy of the middle thoracic spine (t5-t8) and chest.

This is the third in a series of articles on the spine. The first reviewed the anatomy of the neck. The second reviewed the upper thoracic spine and chest (T1-T4). A fourth article is planned for the lower thoracic spine. Procedures in the midthoracic spine include chest tube placement, trigger point injections, chemodenervation with botulinum toxin, video-assisted thoroscopic surgery, and spinal injections. Complications include pneumothorax, hemothorax, diaphragmatic irritation, sympathetic trunk irritation, postthoracotomy pain, and intradural abscesses. This article provides anatomically accurate schematics of innervations of the middle thoracic chest and spine (T5-T8) that can be used to interpret magnetic resonance images of the muscles and nerves. Cross-sectional schematics of the middle thoracic chest and spine were drawn as they appear on imaging projections. The relevant nerves were color coded. The muscles and skin surfaces were labeled and assigned the color of the appropriate nerves. An organized comprehensive map of the motor innervation of the middle thoracic chest and spine allows the physician to increase the accuracy and efficacy of interventional procedures. This could also assist the electromyographer in correlating the clinical and electrophysiologic findings with magnetic resonance images.

Anatomy, Cross-Sectional↗

Supraspinal tonic influence on spinal reflexes and involvement in the effect of chlorpromazine.

Chlorpromazine (CPZ) depressed mono-(MSR) and polysynaptic reflexes in anesthetized rats. The MSR remained unaltered after spinal transection (C1). After spinal transection, the inhibitory effect of CPZ on the MSR disappeared. After CPZ injection, spinal transection enhanced the MSR to pre-drug level. Reserpine pretreatment abolished the inhibitory effect of CPZ on the MSR. Phenoxybenzamine inhibited the MSR and, when pre-injected, markedly attenuated the effect of CPZ on the MSR. These results suggest that in anesthetized rats, CPZ blocks the alpha-adrenoceptor-mediated facilitatory component of the spontaneous tonic influence on the MSR.

Animals↗

Role of spinal microglia in rat models of peripheral nerve injury and inflammation.

Mounting evidence supports the hypothesis that spinal microglia modulate the development and maintenance of some chronic pain states. Here we examined the role of spinal microglia following both peripheral inflammatory insult and peripheral nerve injury. We observed significant ipsilateral dorsal horn microglia activation 2 weeks after injury and bilateral activation 50 days following nerve injury as well as 24 h following intraplantar zymosan but not intraplantar complete Freund's adjuvant (CFA). Ipsilateral but not contralateral microglia activation was associated with hind paw mechanical hyperalgesia. Spinal injection of the glial metabolic inactivator fluorocitrate attenuated ipsilateral hyperalgesia and bilateral spinal microglia activation after peripheral nerve injury. Intrathecal fluorocitrate reversed hyperalgesia after intraplantar zymosan and produced no reversal of CFA-induced hyperalgesia. These data suggest a role for spinal glia in the persistence of mechanical hyperalgesia following peripheral nerve injury. However, activation of spinal microglia contralaterally did not correlate to nociception. Furthermore, it would appear that the time course of microglia activation and their contribution to inflammatory pain is dependent on the inflammatory stimulus administered.

Animals↗