Pain
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Comparative Study
Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat.
To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. ⋯ Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy.
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Comparative Study
Cholinergic modulation of nociceptive responses in vivo and neuropeptide release in vitro at the level of the primary sensory neuron.
Muscarinic acetylcholine receptors (mAChRs) have been widely reported as pharmacological targets for the treatment of pain. However, most of these efforts have focused on CNS mAChRs and their role in modulating nociception at the level of the spinal cord. The present study examines the contribution of peripheral mAChRs in trigeminal nociceptive pathways using a combination of in vivo and in vitro approaches. ⋯ Finally, combined in situ hybridization/immunofluorescence demonstrated that m2 mRNA was present in 20% of trigeminal ganglion neurons between 30 and 60 microm in diameter and that 5-9% of these also expressed CGRP or VR1 immunoreactivity. These results show that activation of peripheral M2 receptors produces antinociception in vivo and the inhibition of nociceptor activity in vitro. While histological analyses at the level of the trigeminal neuronal cell bodies leave open the question of whether the effects of M2 agonists are direct or indirect, these data indicate that primary sensory neuronal M2 receptors may represent a viable peripheral target for the treatment of pain and inflammation.
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Comparative Study
Psychosocial factors predictive of occupational low back disability: towards development of a return-to-work model.
This paper focuses on the identification and testing of potential psychosocial factors contributing to an integrated multivariate predictive model of occupational low back disability. Psychosocial predictors originate from five traditions of psychosocial research: psychopathological, cognitive, diathesis-stress, human adaptation and organizational psychology. The psychosocial variables chosen for this study reflect a full range of research findings. ⋯ The key psychosocial predictors identified were expectations of recovery and perception of health change. Also implicated, but to a lesser degree, were occupational stability, skill discretion at work, co-worker support, and the response of the workers' compensation system and employer to the disability. All psychosocial models were better at predicting who will return than who will not return to work.
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Clinical Trial
Initial pharmacokinetic, safety and efficacy evaluation of nasal morphine gluconate for breakthrough pain in cancer patients.
Patients with controlled background pain associated with cancer frequently also experience episodes of moderate to severe intensity breakthrough pain. Opioid pharmacotherapy, particularly with oral morphine, remains the cornerstone for the management of cancer pain. Nasal administration of opioids provides a mechanism for more rapid drug absorption and more rapid onset of pain relief compared with oral dosing. ⋯ Patient satisfaction ratings were high. These results show that nasal morphine has rapid absorption and apparent onset of effect. Additional multi-dose, dose-ranging and placebo-controlled studies of nasal morphine for cancer pain are warranted.