Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain

Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

Calcineurin Regulates Synaptic Plasticity and Nociceptive Transmissionat the Spinal Cord Level

Calcineurin, the predominant Ca2+/calmodulin-dependent serine/threonine protein phosphatase (also known as protein phosphatase 2B), is highly expressed in immune T cells and the nervous system, including the dorsal root ganglion and spinal cord. It controls synaptic transmission and plasticity by maintaining the appropriate phosphorylation status of many ion channels present at presynaptic and postsynaptic sites. As such, normal calcineurin activity in neurons and synapses is mainly involved in negative feedback regulation in response to increased neuronal activity and intracellular Ca2+ levels. Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) are widely used as immunosuppressants in tissue and organ transplantation recipients and for treating autoimmune diseases but can cause severe pain in some patients. Furthermore, diminished calcineurin activity at the spinal cord level may play a major role in the transition from acute to chronic neuropathic pain after nerve injury. Restoring calcineurin activity at the spinal cord level produces long-lasting pain relief in animal models of neuropathic pain. In this article, we provide an overview of recent studies on the critical roles of calcineurin in regulating glutamate NMDA and AMPA receptors, voltage-gated Ca2+ channels, potassium channels, and transient receptor potential channels expressed in the spinal dorsal horn and primary sensory neurons.

Pathophysiology of pain in cancer and other terminal illnesses

Cancer pain involves a myriad of peripheral changes in the function of tissues and nerves, at the site of the tumour growth, as well as a number of consequent changes in the processing of pain messages at the spinal cord level with implications for the pain experience at higher centres. This chapter reviews the changes in peripheral pain signalling, notes the likely prevalence of both inflammatory and neuropathic components, and describes the altered events at spinal levels and within the circuits of pain in higher brain areas that can help explain the ongoing pain, hyperalgesia, and allodynia that patients with cancer and other chronic illnesses, such as HIV/AIDs, experience. The mechanisms of action of therapies, both existing and potential novel approaches, are also described. The importance of these processes in the development and treatment of chronic pain is an emerging issue, particularly as the problem of persistent pain in cancer survivors increases in prevalence.

Comparison of anterior and posterior surgical approaches in multi-level cervical spondylotic myelopathy

Background: Cervical spondylotic myelopathy (CSM) is one of the most common dysfunctions of spinal cord which occurs due to degenerative changes in cervical spine disc and facet joints. The management of multilevel spondylotic myelopathy is always controversial. The posterior approaches are always preferable in multiple level spondylosis. But according to newer studies, anterior approaches have similar results. Aim of the study was to compare the efficacy of posterior and anterior approaches in multilevel cervical myelopathy.Methods: This study includes all patients with multilevel cervical spondylotic myelopathy who have undergone decompression surgery with fusion. Detailed preoperative and post-operative assessment was done according to modified Japanese Orthopedic Association scoring system.Results: Eighty eight patients of CSM surgical cases were selected for this study and 29 cases of multi-level CSM were observed. And they were randomly selected for anterior and posterior approaches. Sixteen cases anterior approach was done either ACDF or Corpectomy with fusion. Mean age of study was 51.63 years with 64 males and 24 females. The spinal cord level at which most surgeries did was C5/6, 62 cases. While at level C4/5, it was 49 and at level C3/4 and C6/7, it was 35 and 36 respectively.Conclusions: Both anterior approach and posterior approaches were associated with betterment in postoperative neurological function for multilevel CSM. And there is no significant advantage in doing anterior approach in multilevel CSM.

A Rare T2-T3 Synovial Facet Cyst Causing Progressive Myelopathy

Intraspinal extradural synovial cysts are a rare occurrence at the spinal cord level and thus a rare cause of myelopathy. Synovial cysts usually present in the more mobile lumbar and cervical parts of the spine; however, they may also arise in the thoracic spine. We present a case of a 59-year-old male with a left upper thoracic synovial cyst at T2-3 causing disabling, progressive myelopathy, and an incomplete spinal cord injury syndrome with inability to ambulate. An urgent decompressive laminectomy with bilateral facetectomies, cyst excision, and posterior fusion was performed. Subsequently, the patient recovered full function. Synovial cysts should be considered in the differential diagnosis of progressive thoracic myelopathy. This is only the sixth reported case of a synovial cyst of this kind occurring between the levels of T1 and T7. Urgent surgical decompression is the recommended treatment.

Corticospinal vs Rubrospinal Revisited: An Evolutionary Perspective for Sensorimotor Integration

The knowledge about how different subsystems participate and interplay in sensorimotor control is fundamental to understand motor deficits associated with CNS injury and movement recovery. The role of corticospinal (CS) and rubrospinal (RS) projections in motor control has been extensively studied and compared, and it is clear that both systems are important for skilled movement. However, during phylogeny, the emerging cerebral cortex took a higher hierarchical role controlling rubro-cerebellar circuits. Here, we present anatomical, neurophysiological, and behavioral evidence suggesting that both systems modulate complex segmental neuronal networks in a parallel way, which is important for sensorimotor integration at spinal cord level. We also highlight that, although specializations exist, both systems could be complementary and potentially subserve motor recovery associated with CNS damage.

Perosomus Elumbis in Piglets: Pathological, Radiological and Cytogenetic Findings

Perosomus elumbis (PE) is a rare congenital condition characterized by agenesis of the lumbar, sacral and coccygeal vertebrae. Perosomus elumbis has rarely been reported in literature as morphological description of singles or few cases. Here we report the first extensive description of eight cases of PE detected in two consecutive litters from the same parents of Casertana pig breed. In August 2018, eight piglets were investigated for multiple malformations. All malformed animals, but one, died in the first day of life. The survivor piglet died at 23 days of age. Pathological, radiological and cytogenetic examination was performed. Furthermore, a farm epidemiological investigation was carried out to investigate the percentage of piglets born dead or with malformations in 2018. The radiological and pathological exams showed skeletal abnormalities at the spinal cord level and visceral malformations. Cytogenetic investigations showed a normal chromosome arrangement. Finally, epidemiological investigation revealed a low prevalence of malformations in newborn pigs, equal to 0.5% of the total birth rate of the farm. Our findings report the first extensive description of PE cases in pigs and suggest an underestimation of this malformation in veterinary medicine. Our findings also suggest a specific genetic etiological basis as cause of PE in pigs and exclude chromosomal abnormalities. Further studies will be performed to confirm this hypothesis.

Stem Cells in the Treatment of Neuropathic Pain: Research Progress of Mechanism

Neuropathic pain (NP) is pain caused by somatosensory nervous system injury or disease. Its prominent symptoms are spontaneous pain, hyperalgesia, and allodynia, and the sense of pain is extremely strong. Owing to the complex mechanism, conventional painkillers lack effectiveness. Recently, research on the treatment of NP by stem cells is increasing and promising results have been achieved in preclinical research. In this review, we briefly introduce the neuropathic pain, the current treatment strategy, and the development of stem cell therapy, and we collected the experimental and clinical trial articles of many kinds of stem cells in the treatment of neuropathic pain from the past ten years. We analyzed and summarized the general efficacy and mechanism of stem cells in the treatment of neuropathic pain. We found that the multiple-mechanism approach was different from the single mechanism of routine clinical drugs; stem cells play a role in peripheral mechanism, central mechanism, and disinhibition of spinal cord level that lead to neuropathic pain, so they are more effective in analgesia and treatment of neuropathic pain.

Reliability of pre-operative diffusion tensor imaging parameter measurements of the cervical spine in patients with cervical spondylotic myelopathy

The present study assessed test–retest and inter-observer reliability of diffusion tensor imaging (DTI) in cervical spondylotic myelopathy (CSM), as well as the agreement among measurement methods. A total 34 patients (12 men, 22 women; mean age, 58.7 [range 45–79] years) who underwent surgical decompression for CSM, with pre-operative DTI scans available, were retrospectively enrolled. Four observers independently measured fractional anisotropy (FA) values twice, using three different measurement methods. Test–retest and inter-observer reliability was assessed using intraclass correlation coefficients (ICCs). Overall, inter-observer agreements varied according to spinal cord level and the measurement methods used, and ranged from poor to excellent agreement (ICC = 0.374–0.821), with relatively less agreement for the sagittal region of interest (ROI) method. The radiology resident and neuro-radiologist group showed excellent test–retest reliability at almost every spinal cord level (ICC = 0.887–0.997), but inter-observer agreements varied from fair to good (ICC = 0.404–0.747). Despite excellent test–retest reliability of the ROI measurements, FA measurements in patients with CSM varied widely in terms of inter-observer reliability. Therefore, DTI parameter data should be interpreted carefully when applied clinically.