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Concept: Intrathecal

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TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1(-/-) mice. The electrophilic metabolites N-acetyl-p-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-p-benzoquinoneimine metabolite L-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1(-/-) mice. Intrathecal injection of a non-electrophilic cannabinoid, Δ(9)-tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. Our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.

Concepts: Neuron, Pain, Sensory system, Paracetamol, Rat, Rodent, Mouse, Intrathecal

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BACKGROUND:: Intrathecal baclofen (ITB) is an effective therapy for spasticity and dystonia in pediatric populations; however, there are associated infectious complications. METHODS:: Patients who had an initial ITB device implanted at our center were followed to determine the proportion of patients with infectious and non-infectious complications, identify risk factors for infection and describe the clinical presentations, treatment and outcomes of infectious complications. RESULTS:: Over the 15 year study period, 139 patients had an initial ITB device placed. The mean age at placement was 13.6 years (range- 6 months to 41 years). In the first year of follow-up, 83% had no complications or secondary procedures, 17% had at least one secondary procedure and 5% had an infectious complication. The median time until infection was 14 days (mean 33 ± 42 days). Patients with secondary spasticity or dystonia were more likely to have infections than patients with cerebral palsy (86% vs.14%; p<0.0001). In the 94 patients with a first secondary procedure, 29% had at least one other procedure and 8% had an infection in the one year follow-up. Overall, 24 patients had 27 infections; 22% superficial, 33% deep and 45% organ space. Staphylococcus aureus was isolated in 50% of those with cultures obtained. Explantation was required in 59% of patients with an infection and differed by infection type: superficial (17%), deep (44%) and organ space (92%) (p=0.004). CONCLUSIONS:: Infectious complications were relatively uncommon; however, when present, frequently led to the explantation of the ITB pump device.

Concepts: Staphylococcus aureus, Infection, Median, Transmission and infection of H5N1, Intrathecal, Spastic diplegia, Intrathecal pump, Baclofen

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Dexmedetomidine, a selective alpha 2-adrenoceptor (α2AR) agonist, has provided significant analgesia in neuropathic pain. However, its underlying molecular mechanism has not been fully elucidated. In the present study, we found that intrathecal administration of dexmedetomidine alleviated mechanical allodynia induced by chronic constriction injury (CCI), and pretreatment with BRL44408 significantly reversed the dexmedetomidine-induced anti-nociceptive effect. Western blotting revealed that dexmedetomidine reduced the activation of microglia and the upregulation of interleukin-18 (IL-18) protein expression in the ipsilateral lumbar spinal dorsal horn, while BRL44408 pretreatment significantly blocked these effects of dexmedetomidine. Immunocytochemistry/immunohistochemistry indicated that the α2A-adrenoceptor was localised to microglia in primary culture, and IL-18 predominantly colocalised with the microglial marker Iba-1 in the dorsal horn of the spinal cord. These results suggest that the IL-18 signalling pathway in microglia may be involved in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI.

Concepts: Present, Molecular biology, Signal transduction, Effect, Pain, Agonist, Intrathecal, Functional selectivity

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BACKGROUND:The epidural test dose, used to identify unintended intrathecal placement, should reliably produce a spinal block without posing a threat to the patient. Most anesthesiologists administer a dose of local anesthetic, commonly lidocaine 45 mg. Pregnant patients are more sensitive to local anesthetics; high and total spinal anesthesia have been reported in the pregnant population with this dose. We hypothesized that lidocaine 30 mg was as effective as lidocaine 45 mg in creating rapid objective evidence of a sensory or motor block.METHODS:In this prospective, randomized, double-blind trial, patients scheduled for cesarean delivery were assigned to 1 of 4 groups: lidocaine 30 mg in the spinal or epidural space, or lidocaine 45 mg by the same routes. A blinded observer assessed the degree of sensory and motor block. The ability to identify intrathecal injection of each dose was compared. Sensory block above T6 dermatome and hypotension were recorded as side effects.RESULTS:Intrathecal administration of lidocaine 30 mg produced rapid subjective and objective signs of neuroblockade within 3 minutes (100%, 95% confidence interval CI, 85%-100% for each). Lidocaine 45 mg produced similar results. All patients in both groups described their legs as warm or heavy after 3 minutes and had a motor block by 5 minutes. On the basis of an intrathecal catheter rate of 1:380, the observed negative predictive value for intrathecal placement if the patient described no sensory changes at 3 minutes was 100% (95% CI, 99.95%-100%) for 30 mg and 100% (95% CI, 99.93%-100%) for 45 mg. We did not identify a decrease in the rate of side effects with the lower dose.CONCLUSIONS:Our results suggest that there is unlikely to be a large difference in the ability of these doses to detect unintentional intrathecal catheter placement. While the negative predictive value for intrathecal injection is very high for both doses, the 95% CI for the sensitivity of either dose is too wide to demonstrate clinical safety to identify all intrathecal catheters. A much larger study is warranted to assess whether there is a lower sensitivity with the 30-mg dose, or a propensity toward high cephalad motor block levels with the 45-mg dose.

Concepts: Childbirth, Randomized controlled trial, Anesthesia, Epidural, Catheter, Intrathecal, Local anesthetic, Spinal anaesthesia

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Although bone cancer pain is common intractable clinical symptom, its underlying mechanisms is still elusive. Accumulating evidence reveals that N-methyl-D- aspartate (NMDA) receptor containing 2B subunit (NR2B) in spinal cord contributes to bone cancer pain. Our preliminary study demonstrated that intrathecal injection of fusion peptide Myr-RC-13 could disrupt spinal KIF17/mLin10 interaction, which is an essential component of KIF17-mediated NR2B transport. Here we report a means by infusion of the selected peptide Myr-RC-13 intrathecally to attenuate bone cancer pain. The results showed that inoculation of fibrosarcoma NCTC 2472 cells into the femur cavity of C3H/HeJ mice induced progressive bone cancer pain and resulted in up-regulation of KIF17 and NR2B in spinal cord. In addition, repetitive spinal delivery of Myr-RC-13 relieved bone cancer-related mechanical allodynia and spontaneous pain behaviors, and down-regulated expression of spinal KIF17 and NR2B. Finally, our results demonstrated that selected peptide Myr-RC-13 was able to attenuate bone cancer pain via decreasing spinal KIF17 and NR2B expression. Therefore, selected peptide Myr-RC-13 might be a potential analgesic strategy for bone cancer pain.

Concepts: Disease, Pain management, Intrathecal

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Background: Intrathecal analgesia and radiofrequency techniques for tumor ablation are employed for palliation of symptoms. These interventions are efficacious in a select number of patients for controlling pain and improving quality of life. Careful selection of an appropriate candidate must be performed to prevent needless, invasive, and costly interventions, as interventional pain management alone will not treat total pain in cancer patients. We describe here a patient who experienced intractable pain and unsuccessfully underwent cordotomy but responded to the interdisciplinary (IDT) palliative care approach in an acute palliative care unit (APCU). Case: A middle-aged female with ovarian cancer metastatic to the left psoas muscle and the supraclavicular and retroperitoneal lymph nodes was admitted with severe left thigh and flank pain. She had been unsuccessfully treated with different opioid regimens, hypogastric nerve block, epidural steroid injection, and cordotomy. The palliative care team was consulted while awaiting placement of an intrathecal pump. The patient was subsequently transferred to the APCU for symptom management and transition to hospice. On admission, her morphine equivalent daily dose (MEDD) was 660 mg. Our IDT-composed of a physician, fellow, nurse practitioner, counselor, chaplain, social worker, and physical and occupational therapists-was able to identify several sources of distress that likely contributed to her expression of pain. Our IDT focused on frequent counseling, improving her function, provided medication education, discussed goals of care, and educated about hospice. She was discharged to hospice care with good pain control and an 85% reduction in her MEDD. Conclusion: An APCU approach involving an IDT alleviated the need for invasive interventions by diagnosing and treating the psychosocial, emotional, and spiritual distress contributing to the patient’s total pain expression. Successful management must be reflective of rigorous assessment of the physical, psychological, spiritual, social, and practical aspects before consideration of more invasive treatments.

Concepts: Cancer, Oncology, Palliative care, Palliative medicine, Hospice, Suffering, Pain management, Intrathecal

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Hyperalgesia and neuroinflammation are associated with glia, which consists of macroglia and microglia. In this study, we used a selective cannabinoid receptor type 2 (CB2) agonist JWH015 to investigate remifentanil-induced postoperative hyperalgesia.

Concepts: Pharmacology, Agonist, Cannabinoid receptor, Glial cell, Microglia, Intrathecal, Functional selectivity, Routes of administration

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Catastrophic errors in healthcare are rare, yet the consequences are so serious that where possible, special procedures are put in place to prevent them. As systems become safer, it becomes progressively more difficult to detect the remaining vulnerabilities. Using inadvertent intrathecal administration of vinca alkaloids as an example, we investigated whether analysis of incident report data describing low-harm events could bridge this gap.

Concepts: Systems theory, Intrathecal, Catastrophe theory

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To determine the minimal electrical threshold (MET) necessary to elicit appropriate muscle contraction when the tip of an insulated needle is positioned epidurally or intrathecally at the L5-6 intervertebral space (phase-I) and to determine whether the application of a fixed electrical current during its advancement could indicate needle entry into the intrathecal space (phase-II) in dogs.

Concepts: Electron, Electromagnetism, Electric charge, Electricity, Electric current, Electrical conductor, Intrathecal, Spinal anaesthesia

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A differential role of endothelin-1 (ET-1) in pain processing has recently been suggested. However, the function of central ET-1 in neuropathic pain (NP) has not been fully elucidated to date. We report here the action of endogenous central ET-1 in sciatic nerve ligation-induced NP (SNL-NP) in a transgenic animal model that over-expresses ET-1 in the astrocytes (GET-1 mice). We hypothesized that the over-expression of astrocytic ET-1 would exert anti-allodynic and anti-hyperalgesic effects in NP, as demonstrated by mechanical threshold and plantar withdrawal latency using the von Frey filament and heat stimuli. In our animal model, GET-1 mice showed an increase in the withdrawal threshold and latency in response to the mechanical and thermal stimuli, respectively, in pain behavior tests after SNL. ET-1 and endothelin type A receptor (ETA-R) levels were increased significantly in L4-L6 segments of the spinal cord (ipsilateral to SNL) of GET-1 mice at 7 and 21days after surgery. Moreover, intrathecal administration of a specific ETA-R antagonist, BQ-123, attenuated the anti-allodynic and anti-hyperalgesic phenotype in GET-1 mice. The effects of BQ-123 on the mRNA expression of extracellular signal-regulated protein kinase1/2 (ERK1/2) and protein kinase B/serine protein kinase (Akt(s)) were assessed in the ipsilateral L4-L6 segments harvested 30minutes after BQ-123 administration on day 7 after surgery. Phosphorylation of ERK1/2 and Akt(s) in the ipsilateral spinal cord of GET-1 mice was reduced following SNL, whereas no reduction was observed after intrathecal injection of BQ-123. In conclusion, our results showed that the over-expression of astrocytic ET-1 reduced SNL-induced allodynia and hyperalgesia by inhibiting the activation of ERK1/2 and Akt(s) via the ETA-R-mediated pathway.

Concepts: Nervous system, Gene, Signal transduction, Adenosine triphosphate, Messenger RNA, Receptor, Pain management, Intrathecal