Trigeminal neuropathic pain (TNP) is a condition that occurs when one or more branches of the trigeminal nerve are insulted. Trigeminal neuropathic pain has been shown to be refractory to treatment. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability in both the peripheral and central nerve systems. Emerging evidence indicates that HCN channels are involved in the development and maintenance of chronic pain, however, the impact of thalamic HCN channel activity on TNP has yet to be elucidated. In this report, we used a chronic constriction of the distal infraorbital nerve (dIoN-CCI) to induce TNP in rats. By infusing HCN channel blockers into the ventral posteromedial (VPM) nucleus of the thalamus in dIoN-CCI rats, we demonstrated that inhibition of HCN channel activity ameliorated TNP. We found that the HCN blocker ZD7288 and the clinical drug ivabradine dose-dependently attenuated both evoked and none-evoked nociceptive behaviors in dIoN-CCI rats. Electrophysiological measurements showed the expression of HCN current (Ih) in the thalamocortical neurons in the VPM was sensitive to the HCN channel modulator cyclic adenosine monophosphate (cAMP), suggesting a contribution of the HCN2 subunit in thalamic HCN current. In the thalamus, surface expression of the HCN2 subunit was increased in dIoN-CCI rats. Taken together, we propose that an increase in HCN channel activity in the thalamus in the ascending nociceptive pathway contributed to trigeminal neuropathic pain.

Alexithymia represents a deficit in identifying and expressing emotions, paucity of fantasies, and an externally oriented cognitive style. Currently, numerous studies document that alexithymia and several mental and somatic disorders are significantly related. Several findings also indicate that this association might be caused by alexithymia related dysregulation of neuroendocrine and immune functions. Together these findings indicate that stressors related to alexithymia could underlie the process of neuroendocrine and immune dysregulation that likely may present a significant risk, sustaining and mediating pathogenesis of several disorders and particulary psychosomatic illnesses. In this context, it is also known that several proinflammatory cytokines may play a role in pain generation and that alexithymia is significantly associated with pain symptoms in several pain disorders. Following these findings this study includes several new data developing current state of the art and showing some alexithymia specific changes in patients with neurological disorders. Main finding of this study shows that alexithymia and anxiety in their specific interactions are linked to increased levels of interleukine-8 (IL-8) in cerebrospinal fluid (CSF) in the group of patients with non-inflammatory neurological...

Neuropathic pain in a common problem encountered in palliative care. When neuropathic pain is diagnosed, appropriate treatment is important in limiting the severe psychosocial impairment that can ensue with undertreated pain. Proper evaluation of the patient to clarify the type of pain experienced is the first step to determine appropriate management. Tapentadol is an oral mu-opioid receptor agonist and a noradrenaline reuptake inhibitor developed by Ortho-McNeil Janssen Pharmaceuticals and approved by the Food and Drug Administration in November 2008 for the treatment of moderate-to-severe acute pain in adult patients and for chronic pain in August 2011 in an extended release form. Tapentadol has been studied for use in nociceptive pain but few studies have yet been done to assess its efficacy in the treatment of neuropathic pain.

Revealing causal structures from observational data is an essential task in many data analysis issues across various domains, such as natural sciences, business, and healthcare. In healthcare, neuropathic pain is one of the most common medical problems, whose diagnosis process has well-understood causal structures. Causal structures are commonly visualized as a directed acyclic graph (DAG) or a node-link diagram, in which nodes represent variables, and edges represent causal relationships between data dimensions. However, these simple static graphs do not convey sufficient information for either an intuitive interpretation for novel viewers, or an in-depth exploration for experts. In this study, the visualization of causal structures for neuropathic pain diagnosis is set into context. An interactive system that integrates application-specific visualization, i.e. a discomfort drawing and a spinal cord diagram, into causality visualization is developed. It is further evaluated by a domain expert on neuropathic pain and a researcher in causal discovery through semi-structured interviews. The results show that the system reveals the causal structures for neuropathic pain diagnosis in a more intuitive, efficient way, and conveys more focused information compared to traditional node-link diagrams. The system is also demonstrated to be helpful to the medical community in neuropathic pain diagnosis, not only for doctors but also for patients. / Att upptäcka kausala strukturer från observationsdata är en viktig uppgift i många dataanalysfrågor inom olika områden, t.ex. naturvetenskap, affärsverksamhet och sjukvård. Inom hälso- och sjukvården är neuropatisk smärta ett av de vanligaste medicinska problemen. Dess diagnosprocess har väl förstådda kausala strukturer. Kausala strukturer visualiseras vanligtvis som en riktad acyklisk graf (DAG) eller nätverksdiagram, där noder representerar variabler och kanter representerar kausala relationer mellan datadimensioner. Dessa enkla statiska grafer förmedlar dock inte tillräckligt information för att ge en intuitiv tolkning för nya betraktare eller en djupgående utforskning för experter. I den här studien sätts visualiseringen av kausala strukturer för diagnostisering av neuropatisk smärta i ett sammanhang. Ett interaktivt system som integrerar applikationsspecifik visualisering, dvs. en smärtteckning och ett ryggmärgsdiagram, i kausalitetsvisualisering utvecklas. Det utvärderas av en domänexpert på neuropatisk smärta och en forskare inom kausal upptäckt genom semistrukturerade intervjuer. Resultaten visar att systemet avslöjar kausalstrukturer för diagnos av neuropatisk smärta på ett mer intuitivt och effektivt sätt och förmedlar mer fokuserad information jämfört med traditionella diagrammer. Systemet har också visat sig vara till hjälp för det medicinska samfundet vid diagnostisering av neuropatisk smärta, inte bara för läkare utan även för patienter.

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Syfte: Det behövs mer forskning inom diagnostik för orofacial smärta. Syftet med studien är att undersöka om den subjektiva bedövningsupplevelsen som erhålls vid aktiv anestesi kan jämföras med den som erhålls vid injektion av aktiv placebo, samt om aktiv placebo påverkar smärttröskel samt smärtkänslighet vid stickstimuli hos friska individer. Material och metod: 31 friska deltagare randomiserades i tre grupper. En grupp fick aktiv injektion (Xylocain 2,0 %), en grupp fick aktiv placebo injektion (Xylocain 0,1%) och en grupp fick icke aktiv placebo (fysiologisk koksaltlösning). Deltagarna utsattes för tre intraorala tester före och efter injektion som mätte mekaniskt beröringsstimuli, smärta vid stickstimuli, smärttröskel samt stimuluskvalitet. Deltagarna fick efter injektion gradera sin bedövningsupplevelse på en 0-10 NRS skala. Resultaten analyserades med parat T-test, ANOVA One-Way, post-hoc T-test med Bonferronickorrektion samt Fishers exakta test. P<0,05 ansågs vara statistiskt signifikant. Resultat: Bedövningsupplevelsen i gruppen aktiv placebo skilde sig signifikant från aktiv injektion (p<0,001) men inte från icke-aktiv placebo (p=0,980). Sticksmärttröskeln vid aktiv placebo skilde sig signifikant från aktiv injektion (p<0,001) men inte från inaktiv placebo (p = 0,052). Smärtintensitet vid stickstimuli skilde sig signifikant mellan före och efter injektion inom gruppen aktiv injektion (p=0,035) men inte för aktiv placebo (p = 0,690) och icke-aktiv placebo (p = 0,726).Slutsats: Ingen skillnad sågs mellan icke-aktiv placebo och aktiv placebo i förmågan att förändra friska deltagares smärttröskel samt smärtkänslighet för stickstimuli och samtidigt ge en upplevelse hos deltagaren om att vara bedövad. Aktiv placebo gav alltså ingen fördel framför icke aktiv placebo. 0,1 % Xylocain uppfyller inte de krav som kan ställas på en bra aktiv placebo. / Aim: More research is needed in diagnostics of orofacial pain. Investigating whether the subjective anesthetic experience obtained in active anesthesia can be compared to that obtained with the injection of active placebo, and whether active placebo affects pain threshold and pain sensitivity under a piercing stimulus in healthy individuals.Materials and Methods: 31 healthy subjects were randomized into three groups. One group received active injection (Xylocain 2.0 %), one group received active placebo (Xylocain 0.1 %) and one group received non-active placebo (physiological saline). The participants were subjected to three intraoral tests before and after injection, which measured allodynia, pain sensitivity under a piercing stimulus, pain threshold and stimulus quality. Participant appreciated their anesthetic experience on a 0-10 NRS scale after injection.Results: The anesthetic experience in the active placebo group was significantly different from active injection (p <0.001) but not from non-active placebo (p=0.980). The pain threshold at active placebo was significantly different from active injection (p <0.001) but not from non-active placebo (p = 0.052). Pain intensity in stick stimuli was significantly different between pre- and post-injection within the active injection group (p =0.035) but not for active placebo (p = 0.690) and non-active placebo (p = 0.726).Conclusion: The study found no difference between non-active placebo and active placebo in the ability to alter healthy participant's pain threshold and pain sensitivity under a piercing stimulus and at the same time give the participant an experience of being anesthetized. 0.1% Xylocain does not meet the requirements for a good active placebo.

<p>Based on the concept that the tactile hypersensitivity and the central sensitization observed in animal models of peripheral neuropathy are maintained by peripheral drive from primary sensory neurons, the present project measured the changes in electrophysiological, immunohistochemical, and pharmacological properties of the dorsal root ganglia (DRG) neurons induced by a peripheral neuropathy. The aim of this study was to make a systematic survey and a unique understanding of changes that occur in primary sensory neurons that can sustain peripheral drive in this model. The data of this study indicate a prominent role of large diameter Aβ-fibers, including low threshold mechanoreceptors in peripheral neuropathy.</p> / Doctor of Philosophy (Medical Science)

Following peripheral nerve transection and microsurgical repair (PNIr) most patients retain significant sensorimotor impairments, a proportion of which also develop chronic neuropathic pain. Individual psychological factors may contribute to the development, intensity and duration of chronic pain. Furthermore, a large body of evidence has indentified beneficial and maladaptive cortical plasticity following disease or injury. The general aim of this thesis was to determine the extent of sensory and motor recovery, functional and structural brain changes, and the impact of chronic neuropathic pain on sensorimotor outcomes following upper limb PNIr. Towards this main aim a sensorimotor psychophysical assessment (that included psychological assessments), nerve conduction testing, and an MRI session that examined brain function and structure was performed in patients with peripipheral nerve injury induced neuropathic pain (PNI-P) and those with no neuropathic pain (PNI-NP). Nerve conduction testing demonstrated that all patients had incomplete peripheral nerve regeneration, and that PNI-P patients had worse sensory nerve regeneration. Psychophysical assessment confirmed that all PNIr patients had significant sensorimotor deficits. Additionally, deficits on tests of vibration detection, sensorimotor integration, and fine dexterity were significantly greater in PNI-P patients. Psychological measures clearly distinguished PNI-P from PNI-NP and healthy controls (HC). Vibrotactile stimulation of the deafferented territory in PNI-NP patients results in reduced BOLD activation within the primary and secondary somatosensory cortices. Interestingly, the regions of reduced BOLD corresponded with gray matter thinning which was negatively correlated with behavioural measures of sensory recovery. Structural abnormalities were also identified in the right insula. PNI-P patients had thinning within the right middle insula and a corresponding decrease in white matter pathways projecting into/out of that region. PNI-P patients also had white matter abnormalities in pathways feeding into/out of the contralesional primary somatosensory cortex and thalamus. In conclusion, PNIr is clearly associated with sensorimotor impairments and brain plasticity. Furthermore, neuropathic pain is associated with worse peripheral nerve regeneration, sensorimotor deficits, different psychological profiles, and structural alterations in brain regions involved in pain perception and somatosensation. These results provide insight into peripheral regeneration, the development of chronic pain, brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.

Following peripheral nerve transection and microsurgical repair (PNIr) most patients retain significant sensorimotor impairments, a proportion of which also develop chronic neuropathic pain. Individual psychological factors may contribute to the development, intensity and duration of chronic pain. Furthermore, a large body of evidence has indentified beneficial and maladaptive cortical plasticity following disease or injury. The general aim of this thesis was to determine the extent of sensory and motor recovery, functional and structural brain changes, and the impact of chronic neuropathic pain on sensorimotor outcomes following upper limb PNIr. Towards this main aim a sensorimotor psychophysical assessment (that included psychological assessments), nerve conduction testing, and an MRI session that examined brain function and structure was performed in patients with peripipheral nerve injury induced neuropathic pain (PNI-P) and those with no neuropathic pain (PNI-NP). Nerve conduction testing demonstrated that all patients had incomplete peripheral nerve regeneration, and that PNI-P patients had worse sensory nerve regeneration. Psychophysical assessment confirmed that all PNIr patients had significant sensorimotor deficits. Additionally, deficits on tests of vibration detection, sensorimotor integration, and fine dexterity were significantly greater in PNI-P patients. Psychological measures clearly distinguished PNI-P from PNI-NP and healthy controls (HC). Vibrotactile stimulation of the deafferented territory in PNI-NP patients results in reduced BOLD activation within the primary and secondary somatosensory cortices. Interestingly, the regions of reduced BOLD corresponded with gray matter thinning which was negatively correlated with behavioural measures of sensory recovery. Structural abnormalities were also identified in the right insula. PNI-P patients had thinning within the right middle insula and a corresponding decrease in white matter pathways projecting into/out of that region. PNI-P patients also had white matter abnormalities in pathways feeding into/out of the contralesional primary somatosensory cortex and thalamus. In conclusion, PNIr is clearly associated with sensorimotor impairments and brain plasticity. Furthermore, neuropathic pain is associated with worse peripheral nerve regeneration, sensorimotor deficits, different psychological profiles, and structural alterations in brain regions involved in pain perception and somatosensation. These results provide insight into peripheral regeneration, the development of chronic pain, brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.