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Neuropathic pain is a common problem in clinical practice, affecting patients physically, emotionally, financially, and socially. Current treatment includes antidepressants, antiepileptics, and opioid analgesics. Bupropion is a specific inhibitor of neuronal noradrenaline reuptake and a weak inhibitor of dopamine reuptake, which shows some promise in the treatment of neuropathic pain.

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Rationale. For centuries, medications derived from the marijuana plant have been used for therapeutic purposes across numerous cultures. In 1964, the primary psychoactive ingredient in cannabis, delta-9-tetrahydrocannabinol (-9-THC) was defined. This, followed by the discovery of the endocannabinoid system, marked the beginning of comprehensive research into the beneficial exploitation of this system. The cannabis plant contains various other cannabinoids besides -9-THC. Most of the effects of cannabinoid-based therapies are based on the agonistic action of -9-THC through cannabinoid receptors. Alternatively, some of these effects are caused by the actions of other cannabinoids, like cannabidiol, which does not have high affinity for cannabinoid receptors. Like -9-THC, cannabidiol (CBD), the non-psychoactive phytocannabinoid in Cannabis sativa, has been hypothesized to ameliorate adverse effects of -9-THC. Cannabidiol possesses neuroprotective, antiemetic, and anti-inflammatory properties. Sativex, a 1:1 ratio of CBD and -9-THC, is currently an approved medication in Europe for the treatment of conditions such as neuropathic pain, and has been fast tracked by the USFDA for late stage clinical trials for a host of disorders, ranging from epilepsy to irritable bowel disease. Additionally, increasing preclinical evidence demonstrates that treatment with Cannabidiol alone produces efficacy on a variety of nervous system injuries, including neuropathic pain, schizophrenia and anxiety disorders. Furthermore, there is mounting evidence of an “entourage effect” in cannabinoid-based pharmacotherapies. This effect occurs when treatment with a combination of cannabinoids derived from the plant produce more efficacy than treatment with a single cannabinoid (1). As cannabinoid-based treatments continue to develop and clinical data increases, further investigation of the entourage effect is necessary to facilitate the appropriate future treatment regimens for nervous system disorders. Hypotheses. We hypothesized that treatment with the non-psychoactive cannabis compound cannabidiol would be as effective as the psychoactive cannabis compound -9-THC, or a combination of the two, in mitigating neuropathic pain in a mouse model of chemotherapy-induced peripheral neuropathy. We additionally hypothesized that cannabidiol would not affect classic cannabinoid-agonist induced cognitive impairment in rodent models of learning and memory. Methodology. Neuropathic pain was induced by repeated injections of the chemotherapeutic agent Paclitaxel. Mechanical hypersensitivity to Paclitaxel was assessed using the Von Frey assay. Cognition was assessed using three rodent models of learning and memory: 1) Conditional Discrimination, 2) Conditional Discrimination with a reversal component, and 3) Barnes Maze. Results. Cannabidiol was found to be more potent and more effective than -9-THC in attenuating neuropathic pain in a dose dependent manner. Combinations of CBD+-9-THC revealed that lower, ineffective doses of CBD and -9-THC display supra-additive effects when given in combination while higher, individually effective doses exhibit sub-additive effects in combination. Cognitively, no deficits were observed over a range of doses of any cannabinoid tested in the conditional discrimination tasks, although a slight trend was observed in animals administered the synthetic mixed CB1/CB2 agonist WIN55,212-2. In the Barnes Maze task, treatment with -9-THC alone dose-dependently decreased number of entries and total time spent in the target zone. Cannabidiol did not produce any effects in the Barnes Maze alone, nor did it attenuate the effects seen in animals treated with -9-THC alone. Lastly, -9-THC did not affect total distance traveled or average speed, whereas combination treatment increased both locomotor measurements at all but the highest combination dose. Conclusions. The results of these studies indicate that cannabidiol is more potent than -9-THC in attenuating neuropathic pain. Results of cognitive testing indicate subtle impairment in animals treated with -9-THC and WIN55,212-2 that were not reversed by CBD. / Biomedical Sciences

Bakgrund: Fysisk yoga är globalt populärt. Denna yoga har flera fysiologiska effekter, bland annat smärtlindring. Yogans effekt på neuropatisk smärta är inte tydlig. Enstaka studier visar positivt utfall för smärtlindring i yogagruppen i jämförelse med kontroll. Syftet med studien var att undersöka om och i så fall hur yoga ger en effekt på nociceptiv och neuropatisk smärta. Metod: Studien är en litteraturöversikt. Sökningarna utfördes i PubMed, Scopus samt AMED. Bara RCT-studier inkluderades. PICO formatet formade inklusionskriterierna, patienten skulle ha nociceptiv smärta och/eller neuropatisk smärta, interventionen skulle vara yoga, kontrollen skulle vara ingen eller andra behandlingar och utfallsmått skulle vara VAS smärtskattningsskala eller motsvarande. De inkluderade studierna granskades med PEDro-Scale och skulle vara över 6 poäng totalt. Resultat: Sökningen resulterade i 396 träffar, varav 71 var relevanta. Åtta studier inkluderades i den slutgiltiga granskningen. Fem av studierna visade statistisk signifikant smärtlindring i yogagruppen i jämförelse med kontrollgruppen, två av dem studerade exklusivt neuropatisk smärta och en exkluderade neuropatisk smärta. Sex av de totala studierna exkluderade ej radikulopati. Sju av studierna utfördes på patienter med ländryggssmärta. Konklusion: Yoga visade en smärtlindrande effekt vid neuropatisk och nociceptiv smärta i denna studie. I denna studie var yogans smärtlindrande effekt kortsiktigt och upp till ett halvår. Neuropatisk smärta studeras exklusivt med låg frekvens inom området. Därav krävs vidare forskning inom området för att säkerställa vilken effekt yoga har på neuropatisk smärta över lag.

Satellite glial cells (SGC) are laminar cells that wrap completely around the sensory neuron and are responsible for buffering extracellular K+ after neuronal excitation. A decrease in the potassium buffering capacity of SGC has been associated with neuropathic pain (NP) behavior and apoptosis. This dissertation investigated the role of the potassium buffering capacity and apoptosis of trigeminal satellite glial cells (SGC) in the maintenance and development of orofacial NP in rats using in vivo and in vitro methodologies. In vivo endpoints were evaluated after performing chronic constriction injury (CCI) of the infraorbital nerve (IoN). NP signs and behavior were evaluated at 5, 10, 20 40 and 80 hours after injury. We evaluated the potassium buffering capacity of SGC by measuring the intracellular potassium concentration and protein levels and gene expression of the Kir4.1 and the SK3 potassium channels and gap junction protein connexin 43 (Cx43). We evaluated apoptosis endpoints including protein levels and gene expression of apoptotic related proteins bcl-2, caspase 9, caspase 3 and p53. Results indicate that NP signs developed as early as 5 hours after injury. After PNI, SGC responded by increasing their intracellular potassium concentration and by increasing protein levels of Kir4.1, SK3 and Cx43. Nonetheless, this increase in protein levels was not accompanied by an increase in gene expression. Apoptosis results revealed that SGC decreased protein levels and gene expression of anti-apoptotic protein Bcl-2. Using in vitro methodologies, we developed primary trigeminal SGC cultures and evaluated how a decrease in the intracellular potassium concentration modulates apoptosis induced by the mitochondrial and death receptor pathways. SGC depleted of potassium after hypoosmotic shock showed a significant increase in early apoptosis after incubation with mitochondrial pathway apoptotic inducer staurosporine when compared to SGC with normal intracellular concentration. This research has revealed that SGC respond early to PNI by increasing their potassium buffering capacity. We also determined that the mitochondrial apoptotic pathway might be involved in the trigeminal SGC response to PNI. From our in vitro experiments we have revealed that potassium is an important modulator of apoptosis induced by the mitochondrial pathway in cultured trigeminal SGC. / Ph. D.

The aim of this project was to get insight into mass spectrometry based proteomics, get familiarized with novel techniques, and obtain the operating skills with modern Orbitrap mass spectrometers. In order to achieve this, the proteome changes in neuropathic pain responses corresponding to nerve injury side in individual rat’s spinal cord were explored. We focused in protein identification and quantification of the expressed proteins in 3 different set of samples, SNL, Sham and Naive rats.

Aim of Investigation: The neurological manifestations of Fabry’s disease, a rare, X-linked, multisystem disorder caused by alpha-galactosidase A deficiency and globotriosylceramide (Gb3) accumulation, include both peripheral and central nervous system symptoms. Here we evaluated a prospectively recruited cohort of patients with Fabry’s disease for pain, small nerve fiber function, and skin innervation. Methods: 66 patients (31 male and 35 female) were enrolled&#65292;31 patients were on ERT. All patients underwent quantitative sensory testing (QST), electrophysiological examination, and extra- and transcranial Doppler sonography. For pain and mood assessment standardized questionnaires were used. Skin biopsies were performed at the left distal leg in 38 patients for intraepidermal nerve fiber density (IENFD) assessment. Results: Age at examination did not differ significantly between women (40.2+/-16.2 years) and men (38.9+/-13.8; n.s.). 29/31 male and 19/35 female patients complained of acroparesthesias or neuropathic pain. QST abnormalities indicative of small fiber impairment were found in 26/31 male and 28/35 female patients. Electrophysiological examination of large fibers and autonomic fibers revealed pathological findings in 11/31 male and 3/35 female patients. All patients had normal Doppler sonography results. Indicators for depression were present in 14/31 male and 10/35 female patients. 20/31 male and 18/35 female patients had a skin biopsy, the IENFD was significantly reduced in male (2.0+/-2.8 fibers/mm) compared with female patients (6.7 +/- 4.4 fibers/mm). In 10 patients free from neurological symptoms, QST and IENFD abnormalities were still detected. Follow up examination after one year in 12 patients under ERT (2.1+/-1.7 years) showed improvement in some symptoms and in QST and neurophysiology in six patients with normal renal function. 20/35 female patients older than 40 y had concomitant diseases, while none of the 18 younger female patients did. The corresponding radio in male patients was 5/19 (>=40y) and 2/13 (<40y) respectively. Conclusions: Neuropathic pain and sensory deficits of the distal extremities are common in patients with Fabry’s disease. QST and IENFD analysis are important for early diagnosis of nerve involvement in Fabry’s disease. Small fiber function may improve under ERT in patients without severe renal impairment.

Peripheral sensitisation and central sensitisation are implicated in the development of neuropathic pain with neuroplasticity occurring at multiple levels of the pain pathway. Hypersensitivity of the spinothalamic tract has been described in neuropathic animal models of diabetes. Spinal dorsal horn neurones of diabetic rats exhibit abnormally high spontaneous firing, suggesting an imbalance between excitatory and inhibitory signals converging within this structure. GABAergic neurones within the spinal cord and thalamus are crucial for the transmission of painful stimuli to higher centres of the brain that are involved in pain perception. GABAA receptors (GABAARs) are an important target for many clinical drugs, and certain endogenous neurosteroids act as potent allosteric modulators of these receptors. A developmental change in the rate of exponential decay of GABAergic synaptic events has been observed in other types of neurones and this may be related in part to fluctuations in endogenous neurosteroid tone. The objective of this study was to investigate changes to inhibitory neurotransmission with development in three levels of the pain pathway and to explore potential mechanisms underlying diabetic neuropathy. The whole-cell patch-clamp technique was used on slices of neural tissue. Electrophysiological recordings were obtained from wild type mice between the ages of 6 and 80 days in lamina II of the spinal cord, the nucleus reticularis (nRT) of the thalamus and the cerebral cortex. Recordings were also obtained from mice with diabetic neuropathy (ob/ob and db/db) between the ages of 60 and 80 days. Neurosteroids and their precursors were employed along with compounds that prevented their activity at the GABAAR such as ?-cyclodextrin, which is a barrel-shaped cyclic oligosaccharide with a lipophilic interior that sequesters neurosteroids. Behavioural experiments were also performed using von Frey filaments and the tail flick test to examine mechanical and thermal nociception. Recordings from the spinal cord, the thalamus and the cerebral cortex revealed that the decay time of miniature inhibitory postsynaptic currents are significantly reduced with development. The neurosteroids allopregnanolone and ganaxolone were significantly more effective in neurones from the older mice. In contrast, ?-cyclodextrin had significantly less effect in neurones from the older mice. In mature diabetic mice (ob/ob mice), the endogenous neurosteroid tone is reduced compared to control mice, but certain neurosteroid compounds have a greater effect on the GABAARs of these diabetic mice. In addition, the diabetic mice exhibit mechanical allodynia and hyperalgesia, which is responsive to exogenously applied neurosteroids. These results are consistent with the hypothesis that a dramatic reduction in endogenous neurosteroid tone occurs as development progresses and that this impacts on the exponential decay time of GABAergic mIPSCs within neurones of the pain pathway. The higher neurosteroid tone in the youngest mice may confer a degree of neural protection over the nervous system as it develops. The reduction of endogenous neurosteroid tone in diabetic mice may be associated with their hypersensitivity. It is possible that pregnane-derived neurosteroids may exert analgesic effects in pathological pain states by attempting to restore the physiological GABAergic inhibitory tone that is observed in immature animals.

A Bell in the Storm - Persistent unexplained pain and the language of the uncanny in the creative neurophenomenal reference is a doctoral work comprised of three parts. Part 1 is an exegesis Persistent unexplained pain and the language of the uncanny in the creative neurophenomenal reference; Part 2 is The Plays, A Bell in the Storm (produced by deckchair theatre in May, 2005) and the radio play To Fall Without Landing (produced by the Australian Broadcasting Commission for Radio National in October 2005); and, Part 3 the book of monochord poems, Secrets of the Driftwood.