Metastatic bone cancer causes severe pain that is primarily treated with opioids. A recently developed model of bone cancer pain was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced spontaneous and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or in vivo but increased sarcoma-induced bone destruction and incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity suggesting enhancement of sarcoma-induced osteolysis. Thus, morphine treatment may "add-on" additional mechanisms of pain beyond those induced by sarcoma. Despite the potential clinical significance, the exact mechanisms of opioid-induced hypersensitivity remain unknown. The vanilloid 1 receptor (TRPV1) is a molecular integrator of noxious stimuli. Sustained morphine elicited thermal and tactile hypersensitivity in WT, but not TRPV1 KO mice. Sustained morphine enhanced capsaicin-induced flinching and plasma extravasation in rats, indicating increased activity of these receptors in the periphery. Immunohistochemical studies indicate increase in TRPV1 expression in DRG and sciatic nerve, but not spinal cord, suggesting increased trafficking of TRPV1 channel to the periphery. Possible mechanisms of this enhanced expression and function of TRPV1 channels is activation of p38 MAPK. Sustained intrathecal infusion of p38 MAPK inhibitor prevents morphine-induced hypersensitivity and enhanced capsaicin-induced flinching, indicating the role of p38MAPK in the development of morphine-induced pain, possibly through sensitization of TRPV1 receptors. Acute administration of p38 MAPK inhibitor reversed morphine-induced pain suggesting the importance of p38 MAPK in the maintenance of morphine-induced hypersensitivity, likely through activation of TRPV1 channel. Sustained morphine also up-regulates NGF content in skin, which is then transported to DRG neurons where phosporilation of p38MAPK takes place. Single injection of anti-NGF peptibody blocked the development of morphine-induced hypersensitivity, enhanced capsaicin-induced flinching and plasma extravasation. Co-treatment with these compounds blocks the development of morphine-induced hyperalgesia and may optimize treatment of chronic pain states, like bone cancer pain.

The idea that there exists a describable stimulus or class of stimuli which invariably and predictably produce pain has been challenged repeatedly. Similarly, the "traditional" notion that there is a one to one relation between tissue damage (or any other specifiable stimulus) and pain response has been vigorously opposed (Livingston, 1943, 1953; Beecher, 1959 Melzack, 1961; Melzack & Wall, 1962). However, the concept of a physically describable, and thus measurable, pain producing stimulus plays an essential role in the study of pain perception. The fact that some stimuli which often produce pain do, under specifiable conditions, fail to produce pain permits the study of conditions which alter the effectiveness of pain stimuli. [...]

There is a great need for new analgesics. The current problem in treatment of severe pain is that side effects limit the effectiveness of therapy. Glycine receptors are important in modulation of nociception, suggesting a novel class of analgesics. Previous studies in rats show that intrathecal administration of glycine agonists and amino acids structurally similar to glycine have antinociceptive effects. The effects of isovaline, a unique, non-proteogenic glycine-like aminoacid, have not been studied. Isovaline is absorbed from the gut and transported across the blood-brain-barrier. We examined the hypothesis that isovaline produces antinociception in mice. Administration of strychnine, an antagonist at glycine receptors, into the cisterna magna or lumbar intrathecal space resulted in allodynia, localized to the somatotopic distribution of the trigeminal and lumbar nerves. These findings provided a basis for models of lumbar and trigeminal neuralgia. Racemic isovaline blocked strychnine induced allodynia in both models without apparent side effects. We next investigated the antinociceptive effects of glycine-like amino acids in formalin foot assay, a conventional rodent model of acute and chronic pain. Antinociceptive effects were demonstrated on intrathecal administration of glycine, beta-alanine, and isovaline. Intravenous isovaline produced significant antinociceptive effects in the formalin foot model. The toxicity of isovaline and related amino acids were determined. Exploratory behavior, gait, and responses to stimuli were used to assess sedation. The rotarod test was used to examine central nervous system (CNS) and neuromuscular toxicities of intravenous isovaline. Lumbar administration of glycine and beta-alanine caused scratching and/or lower body weakness. Isovaline at 7-times intrathecal ED50 produced lower body weakness in some animals. None of the amino acids produced sedation comparable to morphine. At 6-times ED50, beta-alanine produced weakness. Both glycine (ED50) and beta-alanine (3x ED50) but not isovaline produced local nerve irritation. Intracisternal injection of glycine did not reverse allodynia and resulted in death. Neither R nor S enantiomers of isovaline impaired performance on the rotarod test. Isovaline has significant antinociceptive properties. Given the absence of apparent CNS or motor toxicity, isovaline has potential as a clinical analgesic.

Procedural pain is still under managed in practice, resulting in immediate and long-term negative sequellae for children. Accreditation guidelines identify health care professionals as responsible for providing procedural pain management, however recent evidence supports the idea that parents can be assisted to provide effective pain management through non-pharmacological strategies. Using Appreciative Inquiry, twelve nurses were interviewed about their knowledge of the evidence, work context, and factors that facilitate their ability to engage parents in procedural pain management. Focus groups verified the findings and made suggestions for practical application. From the data, four predominant patterns emerged: 1) Establishing meaningful interpersonal connections; 2) Fostering a culture of collaboration; 3) Pain as a priority – moving from a philosophy to a standard; 4) Sustaining practices through advanced knowledge and skills. Findings will contribute to the literature that guides education, policies, and standards that engage all resources to promote more effective pain relieving practices.

Neuropathic (NP) pain is a debilitating chronic pain disorder that is a challenge to diagnose and an even greater challenge to treat. Commonly described as burning or shock-like, NP pain is characteristically resistant to traditional analgesic therapy. This thesis project aimed to investigate the potential therapeutic benefit of delta opioid receptor (δOR)-selective agonists in the management of NP pain. In the current experiments, rats that underwent unilateral sciatic nerve injury displayed characteristic behavioural manifestations including cold and thermal hyperalgesia as well as tactile allodynia in the ipsilateral hind paw. The spinal administration of DLT, a δOR-selective agonist, dose-dependently reversed tactile allodynia in NP rats and attenuated cold and thermal hypersensitivities. Moreover, DLT produced greater antinociceptive effects in NP rats compared with controls in the cold water paw withdrawal, hot water tail flick, and thermal plantar box tests. Nerve injury-induced augmentation in δOR function was dependent on nociceptive afferents, since the effect was absent in NP rats that received neonatal treatment with capsaicin. Furthermore, it was not due to increased δOR biosynthesis as western blots and immunohistochemistry revealed no change in spinal δOR protein. We hypothesized that an alternative mechanism, such as redistribution of receptors within the neuron, may underlie δOR function changes. Using immunogold electron microscopy, we showed that nerve injury indeed increased the cell surface expression of δORs within dendritic profiles of the dorsal horn via redistribution of existing receptors. Interestingly, this event was observed bilaterally in the deep dorsal horn, with no effect in the superficial laminae. The mechanisms underlying nerve injury-induced δOR trafficking remain unclear however we may take cues from other δOR trafficking events. We showed that concomitant treatment of rats with morphine and a glial inhibitor prevented both the activation of spinal glia and the changes in δOR agonist effects observed with morphine alone, suggesting that glial activity contributes to morphine-induced δOR trafficking in vivo and may provide insight into the mechanisms underlying nerve injury-induced δOR trafficking. Collectively, these studies reveal an important role of δORs in modulating pain symptoms associated with nerve injury, supporting further exploration of δORs as novel therapeutic targets in the treatment of NP pain. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2009-04-20 14:46:29.83

Shneidman (1993) has theorized that psychache (i.e., intolerable psychological pain) is the key cause of suicide, and accounts for the effect of all other psychological factors. Two studies are presented that test Shneidman’s theory, and compare the influence of psychache on suicidality relative to that of hopelessness. In the first study, a causal hypothesis was examined using a longitudinal design. Undergraduate students (N = 588) completed measures of psychache, hopelessness, and suicide ideation at two time points four months apart. Results supported the hypothesis that psychache has a causal role in suicidality, as change in suicide ideation was predicted by change in psychache. However, the hypothesis that psychache would fully mediate the effect of hopelessness was not supported, as only a small and partial mediation effect was evidenced, and change in hopelessness also contributed unique variance to the prediction of suicide ideation. In a second study, the hypotheses that psychache is necessary and sufficient for suicide were examined. Undergraduate students (N = 1,333) were prescreened for high and low levels of psychache and hopelessness, and those who met cutoff criteria (N = 184) were selected to make up four groups with combinations of these constructs. Groups were compared with respect to various measures of suicide ideation, motivations, and behaviours using one-way multivariate analyses of variance. In general, dependent measures significantly differed by level of psychache, but not by level of hopelessness. This pattern of group differences supported the hypothesis that psychache is necessary for suicide. However, the claim that psychache is sufficient was not consistently supported, as some suicide criteria were significantly elevated only for groups exhibiting high levels of both psychache and hopelessness. Taken together, the results of this dissertation provide strong support for the key role of psychache in suicide and its parity with hopelessness as a statistical predictor of suicidality. These findings improve understanding of the suicidal state of mind, and have important implications for clinical practice. / Thesis (Ph.D, Psychology) -- Queen's University, 2009-11-30 13:33:54.267

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