Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.

Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.

Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.

Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect a person’s quality of life and is often refractory to currently available treatments. In order to advance the field and find effective therapeutic avenues; signs, symptoms, and biomarkers in humans should be identified and related to specific pain-generating mechanisms. The present work utilizes quantitative sensory testing (QST) and magnetic resonance spectroscopy (MRS) to evaluate the relationship between the functional integrity of the dorsal column-medial lemniscus pathway (DCML), the spinothalamic tract (STT), and metabolic markers of neuronal loss and glial activation in the thalamus of persons with/without NP after SCI. This work was based on the hypothesis that the presence/severity of NP after SCI is dependent both on function of ascending somatosensory pathways and changes in neuronal and glial markers in the thalamus. The results indicate that NP is associated with a decreased afferent DCML input to the thalamus resulting in a loss of inhibitory neurons and that residual function from STT afferents may contribute to thalamic glial activation and NP. Based on this work, in combination with previous studies in animals and humans, it can be proposed that NP after SCI partly results from the combination of residual STT function and loss of neuronal inhibition leading to neuronal hyperexcitability in the spinal cord and the thalamus. Thus, the presence of NP in chronic SCI is dependent on several underlying mechanisms which may be measured in human subjects with methods such as QST and MRS. Clinical implications and recommendations for further research are enclosed.

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The rat model of cervical dorsal root injury mimics the avulsion of dorsal roots in humans following brachial plexus injury, a condition that leads to debilitating sensory disturbances and intractable neuropathic pain that is not amenable to repair. This injury disrupts sensory inputs from the dorsal roots to the spinal cord and the damaged axons do not regenerate across the PNS-CNS interface, the dorsal root entry zone. This thesis investigated the role of OECs for repairing DRI-associated neuropathic pain, which has never been previously explored. Chapter 2 of this thesis characterised two DRI models, a partial (2-root) or complete (4-root) deafferentation of the rat forepaw. The 2-root animals developed persistent allodynia and hyperalgesia, whereas in the 4-root DRI, in contrast, reduced sensation (desensitisation) was found within the affected forepaw. The degree of deficits on performing complex, skilled forepaw movements was proportional to the severity of DRI. Sensory control of forepaw movements was permanently abolishes in animals with 4-root DRI. With the goal of repairing DRI-associated neuropathic pain, the efficacy of genetically modified OECs that carry a novel GDNF construct was examined. These modified GDNF-OECs were able to produce GDNF in vitro, however, died rapidly and failed to yield long term GDNF expression after both acute and delayed transplantation into the DRI spinal cord. Unmodified plain OECs were then used. The results show that delayed transplantation of OECs attenuated the development of DRI-associated allodynia and hyperalgesia. Central reorganisations occurred within the dorsal horn following DRI, including reduction in the area of deep dorsal horn, permanent depletion of IB4-labeled axons and restoration of CGRP-labelled afferents in the denervated superficial laminae. The development of neuropathic pain is suggested to be mediated by the aberrant expansion of large myelinated VGLUT1-positive afferents into the superficial laminae, which normally receive nociceptive inputs. The effect of OECs on modulating nociception seems to be mediated by factors other than inhibition of afferent sprouting. In conclusion, the results in this thesis demonstrated the potential effect of OECs for modulating DRI-associated neuropathic pain. This finding could have clinical applicability for resistant pain sequelae resulting from neurotrauma.

Neuropathic pain is defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system". In contrast to physiological pain that warns of noxious stimuli likely to result in tissue damage, neuropathic pain serves no protective function. Examples of neuropathic pain states include postherpetic neuralgia (shingles) and phantom limb / stump pain. This pain state also exists in the orofacial region, with the possibility of several variants including atypical odontalgia and burning mouth syndrome. There is a paucity of information on the prevalence of neuropathic pain in the orofacial region. One study assessed patients following endodontic treatment and found that approximately 3 to 6percent of patients reported persistent pain. Patients predisposed to the condition atypical odontalgia (phantom tooth pain) include those suffering from recurrent cluster or migraine headaches. Biochemical and neurobiological processes leading to a neuropathic pain state are complex and involve peripheral sensitisation, and neuronal plasticity of the central and peripheral nervous systems. Subsequent associated pathophysiology includes regional muscle spasm, sympathetic hyperfunction, and centralisation of pain. The relevant clinical features of neuropathic pain are: (i) precipitating factors such as trauma or disease (infection), (ii) pain that is frequently described as having burning, paroxysmal, and lancinating or sharp qualities, and (iii) physical examination may indicate hyperalgesia, allodynia and sympathetic hyperfunction. The typical patient complains of persistent, severe pain, yet there are no clearly identifiable clinical or radiographic abnormalities. Often, due to the chronicity of the problem, afflicted patients exhibit significant distress and are poor pain historians, thus complicating the clinician's task of obtaining a detailed and relevant clinical and psychosocial history. An appropriate analgetic blockade test for intraoral sites of neuropathic pain is mucosal application of topical anaesthetics. Other, more specific, tests include placebo controlled lignocaine infusions for assessing neuropathic pain, and placebo controlled phentolamine infusions for sympathetically maintained pain. The treatment and management of neuropathic pain is multidisciplinary. Medication rationalisation utilises first-line antineuropathic drugs including tricyclic antidepressants, and possibly an anticonvulsant. Topical applications of capsaicin to the gingivae and oral mucosa are a simple and effective treatment. Neuropathic pain responds poorly to opioid medication. Psychological assessment is often crucial in developing strategies for pain management. Psychological variables include distress, depression, expectations of treatment, motivation to improve, and background environmental factors. To enable a greater understanding of neuropathic pain, thereby leading to improved treatments, high-performance liquid chromatography-mass spectrometry is one analytical technique that has the potential to contribute to our knowledge base. This technique allows drugs and endogenous substances to be assayed from one sample in a relatively short time. The technique can identify, confirm, and measure the concentrations of multiple analytes from a single sample.

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Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. Patch clamp electrophysiology revealed that the intrinsic neuronal excitability of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (N.Acc.) was significantly reduced in those mice. We used tyrosine hydroxylase (TH)-cre mice that were microinjected with adeno-associated virus (AAV) to express channelrhodopsin-2 (ChR2) to allow optogenetic stimulation of VTA dopaminergic neurons in the VTA or in their N.Acc. terminals. Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N.Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.