Accepted

Neuropathic pain in people with spinal cord injury is thought to be due to altered central neuronal activity. A novel therapeutic intervention using virtual reality (VR) head-mounted devices was investigated in this study for pain relief. Given the potential links to neuronal activity, the aim of the current study was to determine whether use of VR was associated with corresponding changes in electroencephalography (EEG) patterns linked to the presence of neuropathic pain. Using a within-subject, randomised cross-over pilot trial, we compared EEG activity for three conditions: no task eyes open state, 2D screen task and 3D VR task. We found an increase in delta activity in frontal regions for 3D VR with a decrease in theta activity. There was also a consistent decrease in relative alpha band (8-12 Hz) and an increase in low gamma (30-45 Hz) power during 2D screen and 3D VR corresponding, with reduced self-reported pain. Using the nonlinear and non-oscillatory method of extracting fractal dimensions, we found increases in brain complexity during 2D screen and 3D VR. We successfully classified the 3D VR condition from 2D screen and eyes opened no task conditions with an overall accuracy of 80.3%. The findings in this study have implications for using VR applications as a therapeutic intervention for neuropathic pain in people with spinal cord injury.

To determine the extent to which quantitative sensory testing (QST) predicted attrition in an interdisciplinary pain program (IPP). Participants (n = 53) enrolled in an IPP completed pretreatment assessments of QST and the PROMIS-29 quality of life survey. Compared with completers, non-completers (24.5%) reported significantly higher pain intensity (7.1, 95% CI [5.8, 8.4] versus 5.4, 95% CI [4.8, 6.1]) and cold hyperalgesia (14.6°C, 95% CI [8.8, 20.4] versus 7.5°C, 95% CI [4.8, 6.1]), with both variables also predicting attrition. This finding highlights a potentially novel and clinically significant use of QST. Higher overall pain intensity and the presence of remote cold hyperalgesia may identify patients at risk for dropping out of an IPP.

Associative learning and memory mechanisms drive interoceptive signaling along the gut-brain axis, thus shaping affective-emotional reactions and behavior. Specifically, learning to predict potentially harmful, visceral pain is assumed to succeed within very few trials. However, the temporal dynamics of cerebellar and cerebral fMRI signal changes underlying early acquisition and extinction of learned fear signals and the concomitant evolvement of safety learning remain incompletely understood. 3T fMRI data of healthy individuals from three studies were uniformly processed across the whole brain and the cerebellum including an advanced normalizing method of the cerebellum. All studies employed differential delay conditioning (N=94) with one visual cue (CS) being repeatedly paired with visceral pain as unconditioned stimulus (US) while a second cue remained unpaired (CS). During subsequent extinction (N=51), all CS were presented without US. Behavioral results revealed increased CS-aversiveness and CS-pleasantness after conditioning and diminished valence ratings for both CS following extinction. During early acquisition, the CS induced linearly increasing neural activation in the insula, midcingulate cortex, hippocampus, precuneus as well as cerebral and cerebellar somatomotor regions. The comparison between acquisition and extinction phases yielded a CS-induced linear increase in the posterior cingulate cortex and precuneus during early acquisition, while there was no evidence for linear fMRI signal changes for the CS during acquisition and for both CS during extinction. Based on theoretical accounts of discrimination and temporal difference learning, these results suggest a gradual evolvement of learned safety cues that engage emotional arousal, memory, and cortical modulatory networks. As safety signals are presumably more difficult to learn and to discriminate from learned threat cues, the underlying temporal dynamics may reflect enhanced salience and prediction processing as well as increasing demands for attentional resources and the integration of multisensory information. Maladaptive responses to learned safety signals are a clinically relevant phenotype in multiple conditions, including chronic visceral pain, and can be exceptionally resistant to modification or extinction. Through sustained hypervigilance, safety seeking constitutes one key component in pain and stress-related avoidance behavior, calling for future studies targeting the mechanisms of safety learning and extinction to advance current cognitive-behavioral treatment approaches.

The 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)-butyric acid, homo-AMPA, an analog of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and 2-aminoadipic acid, has shown no activity towards ionotropic and metabotropic glutamate 1, 2, 3, 4, 5, and 7 receptors (mGluR 1-7), agonist activity at mGluR6 while the activity at mGluR8 was never investigated. The effect of homo-AMPA on pain control has been never investigated. In this study we evaluated the effect of intra-ventrolateral periaqueductal grey (VL PAG) microinjections of homo-AMPA on pain responses and the activity of pain-responding neurons of the rostral ventromedial medulla (RVM), the "pronociceptive" ON cells, and the "antinociceptive" OFF cells. The study was performed in control and diabetic neuropathic mice. Homo-AMPA decreased mechanical allodynia in diabetic neuropathic mice. Homo-AMPA increased also the latency to tail-flick, decreased the ongoing activity, the pain stimulus-evoked burst of firing, and delayed the onset of the burst of the ON cells in both, control and neuropathic mice. Homo-AMPA also increased the ongoing activity, decreased and delayed the pause of the OFF cells in control mice. Unlike the retina, we did not find the transcript and protein for mGluR6 in the VL PAG. Alpha-methyl-serine-O-phosphate, a group III mGluRs antagonist, blocked the anti-allodynic effect of homo-AMPA. Considering the absence of both, mGluR6 in VL-PAG and homo-AMPA activity at mGluR4 and mGluR7 at the dose used, mGluR8 could be the target on which homo-AMPA produces the observed effects. The target of homo-AMPA capable of evoking analgesia at a very low dose and in conditions of diabetic neuropathy deserves further consideration.

This review highlights recent findings of different amplitude ranges, roles, and modulations of A-type K currents (I) in excitatory (GAD67-GFP) and inhibitory (GAD67-GFP) interneurons in mouse spinal cord pain pathways. Endogenous neuropeptides, such as TAFA4, oxytocin, and dynorphin in particular, have been reported to modulate I in these pain pathways, but only TAFA4 has been shown to fully reverse the opposing modulations that occur selectively in LIIo GAD67-GFP and LIIi GAD67-GFP interneurons following both neuropathic and inflammatory pain. If, as hypothesized here, Kv4 subunits underlie I in both GAD67-GFP and GAD67-GFP interneurons, then I diversity in spinal cord pain pathways may depend on the interneuron-subtype-selective expression of Kv4 auxiliary subunits with functionally different N-terminal variants. Thus, I emerges as a good candidate for explaining the mechanisms underlying injury-induced mechanical hypersensitivity.

Burrowing behaviour is employed to assess pain-associated behaviour in laboratory rodents. To gain insight in how models of disease associated persistent pain and analgesics affect burrowing behaviour, we performed a systematic review and meta-analysis of studies that assessed burrowing behaviour. A systematic search in March 2020 and update in September 2020 was conducted in 4 databases. Study design characteristics and experimental data were extracted, followed by a random-effects meta-analysis. We explored the association between burrowing and monofilament-induced limb withdrawal. Dose response relationship was investigated for some analgesics. Forty-five studies were included in the meta-analysis, in which 16 model types and 14 drug classes were used. Most experiments used rat (79%) and male (72%) animals. Somatic inflammation and trauma induced neuropathy models were associated with reduced burrowing behaviour. Analgesics (NSAID and gabapentinoids) attenuated burrowing deficits in these models. Reporting of measures to reduce risk of bias was unclear except for randomisation which was high. There was not a correlation (R2 = 0.1421) between burrowing and monofilament-induced limb withdrawal. Opioids, gabapentin and naproxen showed reduced burrowing behaviour at high doses, while ibuprofen and celecoxib showed opposite trend. The findings indicate that burrowing could be used to assess pain-associated behaviour. We support the use of a portfolio of composite measures including spontaneous and stimulus-evoked tests. The information collected here could help in designing experiments involving burrowing assessment in models of disease associated pain.