Transcriptional changes across tissue and time provide molecular insights into a therapeutic window of opportunity following traumatic stress exposure.

Unfortunately, survivors of traumatic stress exposure (TSE) frequently develop adverse posttraumatic neuropsychiatric sequelae (APNS) such as chronic pain and stress/depressive symptoms. Increasing evidence indicates that there is a 'window of opportunity' following TSE in which therapeutic interventions are most effective against APNS, yet mechanisms accounting for this observation are poorly understood. Here, we aimed to better understand such mechanisms by generating snapshots of the transcriptional landscape in the early aftermath of TSE across tissues and time.

A DNA methylation signature in the stress driver gene Fkbp5 indicates a neuropathic component in chronic pain.

Background: Epigenetic changes can bring insight into gene regulatory mechanisms associated with disease pathogenicity, including chronicity and increased vulnerability. To date, we are yet to identify genes sensitive to epigenetic regulation that contribute to the maintenance of chronic pain and with an epigenetic landscape indicative of the susceptibility to persistent pain. Such genes would provide a novel opportunity for better pain management, as their epigenetic profile could be targeted for the treatment of chronic pain or used as an indication of vulnerability for prevention strategies.

Does epigenetic 'memory' of early-life stress predispose to chronic pain in later life? A potential role for the stress regulator .

Animal behaviours are affected not only by inherited genes but also by environmental experiences. For example, in both rats and humans, stressful early-life events such as being reared by an inattentive mother can leave a lasting trace and affect later stress response in adult life. This is owing to a chemical trace left on the chromatin attributed to so-called epigenetic mechanisms.

The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes.

It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes.

The mitogen and stress-activated protein kinase 1 regulates the rapid epigenetic tagging of dorsal horn neurons and nocifensive behaviour.

Phosphorylation of histone H3 at serine 10 (p-H3S10) is a marker of active gene transcription. Using cognitive models of neural plasticity, p-H3S10 was shown to be downstream of extracellular signal-regulated kinase (ERK) signalling in the hippocampus. In this study, we show that nociceptive signalling after peripheral formalin injection increased p-H3S10 expression in the ipsilateral dorsal horn.

Complex regulation of the regulator of synaptic plasticity histone deacetylase 2 in the rodent dorsal horn after peripheral injury.

Histone deacetylases (HDACs), HDAC2 in particular, have been shown to regulate various forms of learning and memory. Since cognitive processes share mechanisms with spinal nociceptive signalling, we decided to investigate the HDAC2 expression in the dorsal horn after peripheral injury. Using immunohistochemistry, we found that spinal HDAC2 was mainly seen in neurons and astrocytes, with neuronal expression in naïve tissue 2.

The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling.

Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents.

Nonparalytic botulinum molecules for the control of pain.

Local injections of botulinum toxins have been reported to be useful not only for the treatment of peripheral neuropathic pain and migraine but also to cause long-lasting muscle paralysis, a potentially serious side effect. Recently, a botulinum A-based molecule ("BiTox") has been synthesized that retains neuronal silencing capacity without triggering muscle paralysis. In this study, we examined whether BiTox delivered peripherally was able to reduce or prevent the increased nociceptive sensitivity found in animal models of inflammatory, surgical, and neuropathic pain.

Short-term anesthesia inhibits formalin-induced extracellular signal-regulated kinase (ERK) activation in the rostral anterior cingulate cortex but not in the spinal cord.

Background: The rostral anterior cingulate cortex (rACC) has been implicated in the negative affective response to injury, and importantly, it has been shown that activation of extracellular signal-regulated kinase (ERK) signaling in the rACC contributes to the full expression of the affective component of pain in rodents. In this study, we investigated whether administration of anesthesia at the time of injury could reduce phosphorylated-ERK (PERK) expression in the rACC, which might eliminate the negative affective component of noxious stimulation. Intraplantar hindpaw formalin stimulation, an aversive event in the awake animal, was given with or without general isoflurane anesthesia, and PERK expression was subsequently quantified in the rACC using immunohistochemistry.

Could targeting epigenetic processes relieve chronic pain states?

Purpose Of Review: Aberrations in the epigenetic landscape have previously been associated with human diseases such as cancer and schizophrenia, and drugs that target epigenetic processes are currently used as therapeutic agents. This article will review the evidence obtained from animal studies indicating that epigenetic processes might regulate long-term pain states and then discuss the possibility that targeting epigenetic mechanisms might be useful for the management of chronic pain.

Recent Findings: Recent animal studies have reported injury-induced changes in epigenetic processes in the central nervous system.

Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice.

Activated mammalian target of rapamycin (P-mTOR) has been shown to maintain the sensitivity of subsets of small-diameter primary afferent A-nociceptors. Local or systemic inhibition of the mTOR complex 1 (mTORC1) pathway reduced punctate mechanical and cold sensitivity in neuropathic pain and therefore offered a new approach to chronic pain control. In this study, we have investigated the effects of the rapamycin analog temsirolimus (CCI-779) on itch.

Regulation of gene expression and pain states by epigenetic mechanisms.

The induction of inflammatory or neuropathic pain states is known to involve molecular activity in the spinal superficial dorsal horn and dorsal root ganglia, including intracellular signaling events which lead to changes in gene expression. These changes ultimately cause alterations in macromolecular synthesis, synaptic transmission, and structural architecture which support central sensitization, a process required for the establishment of long-term pain states. Epigenetic mechanisms are essential for long-term synaptic plasticity and modulation of gene expression.

Descending controls modulate inflammatory joint pain and regulate CXC chemokine and iNOS expression in the dorsal horn.

Background: Descending control of nociceptive processing, by pathways originating in the rostral ventromedial medulla (RVM) and terminating in the dorsal horn, contributes to behavioural hypersensitivity in a number of pain models. Two facilitatory pathways have been identified and are characterized by serotonin (5-HT) content or expression of the mu opiate receptor. Here we investigated the contribution of these pathways to inflammatory joint pain behaviour and gene expression changes in the dorsal horn.

Synthetic self-assembling clostridial chimera for modulation of sensory functions.

Clostridial neurotoxins reversibly block neuronal communication for weeks and months. While these proteolytic neurotoxins hold great promise for clinical applications and the investigation of brain function, their paralytic activity at neuromuscular junctions is a stumbling block. To redirect the clostridial activity to neuronal populations other than motor neurons, we used a new self-assembling method to combine the botulinum type A protease with the tetanus binding domain, which natively targets central neurons.

Novel molecular correlates of endocannabinoid-mediated fear-conditioned analgesia in rats.

Background: Fear-conditioned analgesia (FCA) is the profound suppression of pain during exposure to conditioned aversive stimuli and is mediated at spinal and supraspinal levels. The endocannabinoid system plays a key role in FCA. This study investigated brain and spinal cord expression of genes implicated in pain- and fear-related plasticity (Zif268 and Sgk1), following expression of formalin-evoked nociception, contextual fear or endocannabinoid-mediated FCA.

Lamina I NK1 expressing projection neurones are functional in early postnatal rats and contribute to the setting up of adult mechanical sensory thresholds.

Background: A small proportion of lamina I neurons of the spinal cord project upon the hindbrain and are thought to engage descending pathways that modulate the behavioural response to peripheral injury. Early postnatal development of nociception in rats is associated with exaggerated and diffuse cutaneous reflexes with a gradual refinement of responses over the first postnatal weeks related to increased participation of inhibitory networks. This study examined the postnatal development of lamina I projection neurons from postnatal day 3 (P3) until P48.

The expression of spinal methyl-CpG-binding protein 2, DNA methyltransferases and histone deacetylases is modulated in persistent pain states.

Background: DNA CpG methylation is carried out by DNA methyltransferases and induces chromatin remodeling and gene silencing through a transcription repressor complex comprising the methyl-CpG-binding protein 2 (MeCP2) and a subset of histone deacetylases. Recently, we have found that MeCP2 activity had a crucial role in the pattern of gene expression seen in the superficial dorsal horn rapidly after injection of Complete Freund's Adjuvant (CFA) in the rat ankle joint. The aim of the present study was to analyse the changes in expression of MeCP2, DNA methyltransferases and a subset of histone deacetylases in the superficial dorsal horn during the maintenance phase of persistent pain states.

Targeting epigenetic mechanisms for pain relief.

Epigenetic changes are chemical modifications to chromatin that modulate gene activity without altering the DNA sequence. While research on epigenetics has grown exponentially over the past few years, very few studies have investigated epigenetic mechanisms in relation to pain states. However, epigenetic mechanisms are crucial to memory formation that requires similar synaptic plasticity to pain processing, indicating that they may play a key role in the control of pain states.

Axonal protein synthesis: a potential target for pain relief?

Research on the role of axonal protein synthesis in the regulation of nociceptive mechanisms has grown significantly over the past four years. Recent advances include evidence that local translation of mRNA can occur in adult primary afferents under the control of the mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase (ERK) signaling pathways. Studies investigating the effect of mTOR and ERK pathway inhibitors in a number of pain models suggest that these signaling pathways may act independently, depending on the type of sensory afferents studied.

Systemic inhibition of the mammalian target of rapamycin (mTOR) pathway reduces neuropathic pain in mice.

The management of neuropathic pain is unsatisfactory, and new treatments are required. Because the sensitivity of a subset of fast-conducting primary afferent nociceptors is thought to be regulated by the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, selectively targeting mTORC1 represents a new strategy for the control of chronic pain. Here we show that activated mTOR was expressed largely in myelinated sensory fibers in mouse and that inhibiting the mTORC1 pathway systemically alleviated mechanical hypersensitivity in mouse models of inflammatory and neuropathic pain.

Injury induced activation of extracellular signal-regulated kinase (ERK) in the rat rostral ventromedial medulla (RVM) is age dependant and requires the lamina I projection pathway.

Descending controls originating in part from the rostral ventromedial medulla (RVM) regulate the excitability of dorsal horn neurons and maintain peripheral pain states. Activation of extracellular signal regulated kinase (ERK) in RVM neurons has been shown following peripheral inflammation and is involved in generating the accompanying inflammatory hyperalgesia. Here, we show that spared nerve injury (SNI), a model of neuropathic pain, results in an increase in ERK activity in RVM neurons of adult rats 3 and 8 days following surgery.

Linking MECP2 and pain sensitivity: the example of Rett syndrome.

Recent animal studies suggest links between MeCP2 function and sensitivity to pain. This study investigated the nature and prevalence of atypical pain responses in Rett syndrome and their relationships with specific MECP2 mutations. Families enrolled in the Australian Rett Syndrome Database (ARSD) and InterRett database participated in this study.

Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury.

Background: Neuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth.