New Perspectives in the Pathophysiology and Treatment of Pain in Patients with Dry Eye Disease

Ocular discomfort and eye pain are frequently reported by patients with dry eye disease (DED), and their management remains a real therapeutic challenge for the Ophthalmologist. In DED patients, injury at the level of each structure of the ocular surface can determine variable symptoms, ranging from mild ocular discomfort up to an intolerable pain evoked by innocuous stimuli. In refractory cases, the persistence of this harmful signal is able to evoke a mechanism of maladaptive plasticity of the nervous system that leads to increased pain responsiveness. Peripheral and, subsequently, central sensitization cause nociceptor hyperexcitability and persistent pain perception that can culminate in the paradoxical situation of perceiving eye pain even in the absence of ocular surface abnormalities. Effective therapeutic strategies of these cases are challenging, and new options are desirable. Recently, a theoretical novel therapeutic approach concerns enkephalins thanks to the evidence that eye pain sensations are modulated by endogenous opioid peptides (enkephalins, endorphins and dynorphins). In this regard, new topical agents open up a new theoretical scenario in the treatment of ocular discomfort and eye pain in the setting of DED, such as, for example, a multimolecular complex based on proteins and glycosaminoglycans also containing opiorphin that may assist the physiological pain-relieving mechanism of the eye.

A Therapeutic Matrix: Virtual Reality as a Clinical Tool for Spinal Cord Injury-Induced Neuropathic Pain

Neuropathic pain (NP) is a chronic, debilitating, and resistant form of pain. The onset rate of NP following spinal cord injuries (SCI) is high and may reduce the quality of life more than the sensorimotor loss itself. The long-term ineffectiveness of current treatments in managing symptoms and counteracting maladaptive plasticity highlights the need to find alternative therapeutic approaches. Virtual reality (VR) is possibly the best way to administer the specific illusory or reality-like experience and promote behavioral responses that may be effective in mitigating the effects of long-established NP. This approach aims to promote a more systematic adoption of VR-related techniques in pain research and management procedures, highlighting the encouraging preliminary results in SCI. We suggest that the multisensory modulation of the sense of agency and ownership by residual body signals may produce positive responses in cases of brain-body disconnection. First, we focus on the transversal role embodiment and how multisensory and environmental or artificial stimuli modulate illusory sensations of bodily presence and ownership. Then, we present a brief overview of the use of VR in healthcare and pain management. Finally, we discus research experiences which used VR in patients with SCI to treating NP, including the most recent combinations of VR with further stimulation techniques.

Reactive astrocytes prevent maladaptive plasticity after ischemic stroke

Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP−/−Vim−/−). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted MRI and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP−/−Vim−/− mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes are required for optimal recovery-promoting plasticity responses after ischemic stroke.

A New Definition of Poststroke Spasticity and the Interference of Spasticity With Motor Recovery From Acute to Chronic Stages

The relationship of poststroke spasticity and motor recovery can be confusing. “True” motor recovery refers to return of motor behaviors to prestroke state with the same end-effectors and temporo-spatial pattern. This requires neural recovery and repair, and presumably occurs mainly in the acute and subacute stages. However, according to the International Classification of Functioning, Disability and Health, motor recovery after stroke is also defined as “improvement in performance of functional tasks,” i.e., functional recovery, which is mainly mediated by compensatory mechanisms. Therefore, stroke survivors can execute motor tasks in spite of disordered motor control and the presence of spasticity. Spasticity interferes with execution of normal motor behaviors (“true” motor recovery), throughout the evolution of stroke from acute to chronic stages. Spasticity reduction does not affect functional recovery in the acute and subacute stages; however, appropriate management of spasticity could lead to improvement of motor function, that is, functional recovery, during the chronic stage of stroke. We assert that spasticity results from upregulation of medial cortico-reticulo-spinal pathways that are disinhibited due to damage of the motor cortex or corticobulbar pathways. Spasticity emerges as a manifestation of maladaptive plasticity in the early stages of recovery and can persist into the chronic stage. It coexists and shares similar pathophysiological processes with related motor impairments, such as abnormal force control, muscle coactivation and motor synergies, and diffuse interlimb muscle activation. Accordingly, we propose a new definition of spasticity to better account for its pathophysiology and the complex nuances of different definitions of motor recovery.

Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced maladaptive plasticity

Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder (SUD). Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. By attenuating H3Q5dop during abstinence, we both altered gene expression programs associated with heroin withdrawal and reduced heroin-primed reinstatement behavior. These findings thus establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in opioid-induced plasticity in VTA.

Dynamic structural neuroplasticity during and after epileptogenesis in a pilocarpine rat model of epilepsy

Background The role of neuroplasticity in epilepsy has been widely studied in experimental models and human brain samples. However, the results are contradictory and it remains unclear if neuroplasticity is more related to the cause or the consequence of epileptic seizures. Clarifying this issue can provide insights into epilepsy therapies that target the disease mechanism and etiology rather than symptoms. Therefore, this study was aimed to investigate the dynamic changes of structural plasticity in a pilocarpine rat model of epilepsy. Methods A single acute dose of pilocarpine (380 mg/kg, i.p.) was injected into adult male Wistar rats to induce status epilepticus (SE). Animal behavior was monitored for 2 h. Immunohistochemical staining was performed to evaluate neurogenesis in the CA3 and dentate gyrus (DG) regions of hippocampus using biomarkers Ki67 and doublecortin (DCX). The Golgi-Cox method was performed to analyze dendritic length and complexity. All experiments were performed in control rats (baseline), at 24 h after SE, on day 20 after SE (latent phase), after the first and 10th spontaneous recurrent seizures (SRS; chronic phase), and in non-epileptic rats (which did not manifest SRS 36 days after pilocarpine injection). Results SE significantly increased the number of Ki67 and DCX-positive cells, suggesting neurogenesis during the latent phase. The dendritic complexity monitoring showed that plasticity was altered differently during epilepsy and epileptogenesis, suggesting that the two processes are completely separate at molecular and physiological levels. The numbers of spines and mushroom-type spines were increased in the latent phase. However, the dendritogenesis and spine numbers did not increase in rats that were unable to manifest spontaneous seizures after SE. Conclusion All parameters of structural plasticity that increase during epileptogenesis, are reduced by spontaneous seizure occurrence, which suggests that the development of epilepsy involves maladaptive plastic changes. Therefore, the maladaptive plasticity biomarkers can be used to predict epilepsy before development of SRS in the cases of serious brain injury.