Bradley J. Kerr

The neuropoietic cytokine family in development, plasticity, disease and injury.

Neuropoietic cytokines are well known for their role in the control of neuronal, glial and immune responses to injury or disease. Since this discovery, it has emerged that several of these proteins are also involved in nervous system development, in particular in the regulation of neurogenesis and stem cell fate. Recent data indicate that these proteins have yet more functions, as key modulators of synaptic plasticity and of various behaviours. In addition, neuropoietic cytokines might be a factor in the aetiology of psychiatric disorders.

Functional Recovery after Peripheral Nerve Injury is Dependent on the Pro-Inflammatory Cytokines IL-1β and TNF: Implications for Neuropathic Pain

IL-1β and TNF are potential targets in the management of neuropathic pain after injury. However, the importance of the IL-1 and TNF systems for peripheral nerve regeneration and the mechanisms by which these cytokines mediate effects are to be fully elucidated. Here, we demonstrate that mRNA and protein levels of IL-1β and TNF are rapidly upregulated in the injured mouse sciatic nerve. Mice lacking both IL-1β and TNF, or both IL-1 type 1 receptor (IL-1R1) and TNF type 1 receptor (TNFR1), showed reduced nociceptive sensitivity (mechanical allodynia) compared with wild-type littermates after injury. Microinjecting recombinant IL-1β or TNF at the site of sciatic nerve injury in IL-1β- and TNF-knock-out mice restored mechanical pain thresholds back to levels observed in injured wild-type mice. Importantly, recovery of sciatic nerve function was impaired in IL-1β-, TNF-, and IL-1β/TNF-knock-out mice. Notably, the infiltration of neutrophils was almost completely prevented in the sciatic nerve distal stump of mice lacking both IL-1R1 and TNFR1. Systemic treatment of mice with an anti-Ly6G antibody to deplete neutrophils, cells that play an essential role in the genesis of neuropathic pain, did not affect recovery of neurological function and peripheral axon regeneration. Together, these results suggest that targeting specific IL-1β/TNF-dependent responses, such as neutrophil infiltration, is a better therapeutic strategy for treatment of neuropathic pain after peripheral nerve injury than complete blockage of cytokine production.

Neuropathic pain behaviours in a chronic-relapsing model of experimental autoimmune encephalomyelitis (EAE).

Abstract Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). While the primary symptoms of MS are losses of sensory and motor functions, it is now recognized that chronic pain is also a major concern affecting between 50% and 80% of MS patients. To date, however, few studies have examined the underlying mechanisms of chronic pain in MS or in the animal model, experimental autoimmune encephalomyelitis (EAE), which shares many features of MS pathology. We, therefore, set out to characterize the changes in pain sensitivity that arises in a chronic‐relapsing model of EAE. We show here that female C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG35–55) develop a robust allodynia to both cold and tactile stimuli. Allodynia emerges early in the disease process, often before any signs of neurological deficit and is independent of the overall symptom severity in these mice. “Classical” cellular substrates for neuropathic pain and allodynia such as altered expression of sensory neuropeptides in the dorsal horn of the spinal do not appear to underlie these changes in sensory function. There is, however, a significant influx of CD3+ T cells and increased astrocyte and microglia/macrophage reactivity in the superficial dorsal horn of mice with MOG35–55 EAE. This suggests that inflammation and reactive gliosis may be key mediators of allodynia in MOG35–55 EAE similar to peripheral nerve and spinal cord injury models. Taken together, our results show that the MOG35–55 EAE model is a useful tool to study neuropathic pain in MS.

Ceruloplasmin Protects Injured Spinal Cord from Iron-Mediated Oxidative Damage

CNS injury-induced hemorrhage and tissue damage leads to excess iron, which can cause secondary degeneration. The mechanisms that handle this excess iron are not fully understood. We report that spinal cord contusion injury (SCI) in mice induces an “iron homeostatic response” that partially limits iron-catalyzed oxidative damage. We show that ceruloplasmin (Cp), a ferroxidase that oxidizes toxic ferrous iron, is important for this process. SCI in Cp-deficient mice demonstrates that Cp detoxifies and mobilizes iron and reduces secondary tissue degeneration and functional loss. Our results provide new insights into how astrocytes and macrophages handle iron after SCI. Importantly, we show that iron chelator treatment has a delayed effect in improving locomotor recovery between 3 and 6 weeks after SCI. These data reveal important aspects of the molecular control of CNS iron homeostasis after SCI and suggest that iron chelator therapy may improve functional recovery after CNS trauma and hemorrhagic stroke.

The transition from acute to chronic pain: understanding how different biological systems interact

PurposeAlthough pain is an adaptive sensory experience necessary to prevent further bodily harm, the transition from acute to chronic pain is not adaptive and results in the development of a chronic clinical condition. How this transition occurs has been the focus of intense study for some time. The focus of the current review is on changes in neuronal plasticity as well as the role of immune cells and glia in the development of chronic pain from acute tissue injury and pain.Principal findingsOur understanding of the complex pathways that mediate the transition from acute to chronic pain continues to increase. Work in this area has already revealed the complex interactions between the nervous and immune system that result in both peripheral and central sensitization, essential components to the development of chronic pain. Taken together, a thorough characterization of the cellular mechanisms that generate chronic pain states is essential for the development of new therapies and treatments. Basic research leading to the development of new therapeutic targets is promising with the development of chloride extrusion enhancers. It is hoped that one day they will provide relief to patients with chronic pain.ConclusionsA better understanding of how chronic pain develops at a mechanistic level can aid clinicians in treating their patients by showing how the underlying biology of chronic pain contributes to the clinical manifestations of pain. A thorough understanding of how chronic pain develops may also help identify new targets for future analgesic drugs.RésuméObjectifBien que la douleur soit une expérience sensorielle adaptative nécessaire à la prévention d’atteintes corporelles supplémentaires, la transition d’une douleur aiguë à une douleur chronique n’est pas un phénomène adaptatif et entraîne l’apparition d’une condition clinique chronique. Depuis un certain temps, la façon dont cette transition survient fait l’objet d’études poussées. Cet article se concentre sur les changements au niveau de la plasticité neuronale ainsi que sur le rôle des cellules immunitaires et de la glie dans l’apparition de la douleur chronique à partir d’une lésion tissulaire et d’une douleur aiguës.Constatations principalesNotre compréhension des voies complexes qui jouent un rôle dans la transition d’une douleur aiguë vers une douleur chronique continue de s’étendre. Les travaux dans ce domaine ont déjà révélé les interactions complexes entre le système nerveux et le système immunitaire, lesquelles entraînent une sensibilisation périphérique et centrale, des composantes essentielles à l’apparition de douleur chronique. Dans son ensemble, la caractérisation exhaustive des mécanismes cellulaires qui génèrent des états de douleur chronique est essentielle à la mise au point de nouvelles thérapies et de nouveaux traitements. La recherche fondamentale menant à la mise au point de nouvelles cibles thérapeutiques est prometteuse, grâce à la mise au point de molécules favorisant la sortie des ions chlorure des cellules nerveuses, lesquelles permettront peut-être un jour de soulager les patients atteints de douleur chronique.ConclusionUne meilleure compréhension de la façon dont la douleur chronique se manifeste à un niveau mécaniste peut aider les cliniciens à traiter leurs patients en démontrant comment la biologie sous-jacente à la douleur chronique contribue aux manifestations cliniques de la douleur. Une compréhension plus complète de la façon dont la douleur chronique se développe pourrait également nous permettre d’identifier de nouvelles cibles pour les médicaments analgésiques futurs.

HIV-1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain

Painful peripheral neuropathy has become the principal neurological disorder in HIV/AIDS patients. Herein, we investigated the effects of a cytotoxic HIV‐1 accessory protein, viral protein R (Vpr), on the peripheral nervous system (PNS). Host and viral gene expression was investigated in peripheral nerves from HIV‐infected individuals and in HIV‐infected human dorsal root ganglion (DRG) cultures by RT‐PCR and immunocytochemistry. Cytosolic calcium ([Ca2+]) fluxes and neuronal membrane responses were analyzed in cultured DRGs. Neurobehavioral responses and cytokine levels were assessed in a transgenic mouse model in which the vpr transgene was expressed in an immunodeficient background (vpr/RAG1−/−). Vpr transcripts and proteins were detected in peripheral nerves and DRGs from HIV‐infected patients. Exposure of rat or human cultured DRG neurons to Vpr rapidly increased [Ca2+] and action potential frequency while increasing input resistance. HIV infection of human DRG cultures caused neurite retraction (P<0.05), accompanied by induction of interferon‐α (IFN‐α) transcripts (P<0.05). vpr/RAG1−/− mice expressed Vpr together with increased IFN‐α (P<0.05) in the PNS and also exhibited mechanical allodynia, unlike their vpr/RAG1−/− littermates (P<0.05). Herein, Vpr caused DRG neuronal damage, likely through cytosolic calcium activation and cytokine perturbation, highlighting Vprs contribution to HIV‐associated peripheral neuropathy and ensuing neuropathic pain.—Acharjee, S., Noorbakhsh, S., Stemkowski, P. L., Olechowski, C., Cohen, E. A., Ballanyi, K., Kerr, B., Pardo, C., Smith, P. A., Power, C. HIV‐1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain. FASEBJ. 24, 4343–4353 (2010). www.fasebj.org

A Critical Review of Neurobiological Factors Involved in the Interactions Between Chronic Pain, Depression, and Sleep Disruption.

Aims/Objectives/Background:A significant number of people who experience chronic pain also complain of depression and sleep problems. The comorbidities and bidirectional relationships that exist between these ailments are well recognized clinically. Further, all 3 disorders involve similar alterations in structural and functional neurobiology and share common pathophysiological mechanisms. We sought to comprehensively review the research literature regarding common neurobiological factors associated with these complex clinical disorders in order to better understand how they are related and provide further rationale for future clinical and research efforts to appropriately understand and manage them. Methods:A comprehensive review of the existing research literature was conducted in the domains of chronic pain, depression, and sleep. Results:Although the neurobiological underpinnings of these factors are complex and require further investigation, comparable changes are seen in levels of serotonin (5-hydroxytryptamine), proinflammatory cytokines, brain-derived neurotrophic factor, and other transmitters in these disorders. Conclusions:This review is unique as it attempts to cast a broader net over the common neurobiological correlates that exist across these 3 conditions. It highlights the complexity of the interrelationships between these disorders and the importance of increasing our understanding of neurobiological factors associated with them.

Resident glial cell activation in response to perispinal inflammation leads to acute changes in nociceptive sensitivity: Implications for the generation of neuropathic pain

Summary Inflammation of the dorsal spinal cord leads to significant but short‐lived changes in nociceptive sensory thresholds due in part to the maintenance of the blood–spinal cord barrier. Abstract Injury or disease affecting the spinal cord is often accompanied by abnormal, chronic pain. Recent estimates suggest that approximately 60% of patients with multiple sclerosis are affected by significant changes in pain sensitivity or experience ongoing neuropathic pain of unknown etiology. Chronic pain is also a significant concern after direct spinal cord trauma. Inflammatory events and the changes in astrocyte and microglia reactivity at the spinal level in response to injury or disease are now recognized as important processes that can initiate pain hypersensitivity. Changes in the structural integrity or permeability of the blood–brain barrier/blood–spinal cord barrier (BBB/BSCB) can facilitate the inflammatory events that result in these abnormal pain states. It remains unclear, however, whether chronic pain in these disorders is dependent on the influx of peripheral leukocytes or whether changes in the reactivity of resident glial cells within the central nervous system alone are sufficient. To address this question, we generated a model of perispinal inflammation that resulted in significant changes in the reactivity of resident astrocytes and microglia within the spinal cord but maintained the integrity of the BSCB. A number of similar changes at the behavioural and cellular level occur in this model that mimic the responses seen in animal models of multiple sclerosis or spinal cord injury (SCI). However, these changes are short lived and resolve over the course of a 2‐week observation period. Our findings suggest that the chronicity of pain after injury or disease in the nervous system is dependent on the integrity of the BBB/BSCB.

A diminished response to formalin stimulation reveals a role for the glutamate transporters in the altered pain sensitivity of mice with experimental autoimmune encephalomyelitis (EAE).

&NA; Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) in which neuropathic pain is now recognized as a major symptom. To date, few studies have examined the underlying mechanisms of neuropathic pain in MS. Recently we showed that in a chronic‐relapsing animal model of MS, experimental autoimmune encephalomyelitis (EAE), characteristic neuropathic behaviours develop. However, responses to persistent noxious stimuli in EAE remain unexplored. We, therefore set out to characterize the changes in pain sensitivity in our EAE model to subcutaneous injection of formalin. We show here that female C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG35–55) display a significant decrease in elicited pain behaviours in response to formalin injection. These effects were found to involve dysregulation of the glutamatergic system in EAE. We show here that these effects are mediated by decreased glutamate transporter expression associated with EAE. Our findings demonstrate that dysregulation of glutamate transporter function in EAE mice is an important mechanism underlying the abnormal pain sensitivity in response to persistent noxious stimulation of mice with EAE and also sheds light on a potential mechanism underlying neuropathic pain behaviours in this model.

Changes in nociceptive sensitivity and object recognition in experimental autoimmune encephalomyelitis (EAE).

Multiple sclerosis is associated with a high incidence of depression, cognitive impairments and neuropathic pain. Previously, we demonstrated that tactile allodynia is present at disease onset in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We have now monitored changes in object recognition in mice with EAE to determine if altered nociceptive sensitivity is also associated with behavioral signs indicative of cognitive impairment in this model. At the onset of clinical signs, mice with EAE showed impairments in the novel object recognition (NOR) assay, indicative of deficits in cognitive functioning early in the disease course. At the spinal level, we found increased gene expression for the cytokines IL-1β, IL-6 and the glutamate transporter EAAT-2 that coincide with increased nociceptive sensitivity and deficits in object recognition. Increased levels of EAAT-2 mRNA appear to be a response to perturbed protein levels of the transporter as we found a loss of EAAT-2 protein levels in the spinal cord of EAE mice. To determine if changes in the levels of EAAT-2 were responsible for the observed changes in nociceptive sensitivity and cognitive deficits, we treated EAE mice with the β-lactam antibiotic ceftriaxone, an agent known to increase glutamate transporter levels in vivo. Ceftriaxone prevented tactile hypersensitivity and normalized performance in the NOR assay in EAE mice. These findings highlight the important interrelationship between pain and cognitive function in the disease and suggest that targeting spinally mediated pain hypersensitivity is a novel therapeutic avenue to treat impairments in other higher order cortical processes.