Pain
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Spinal cord fMRI offers an excellent opportunity to quantify nociception using neuronal activation induced by painful stimuli. Measurement of the magnitude of stimulation-induced activation, and its suppression with analgesics can provide objective measures of pain and efficacy of analgesics. This study investigates the feasibility of using spinal cord fMRI in anesthetized rats as a pain assay to test the analgesic effect of locally and systemically administered lidocaine. ⋯ Local administration of lidocaine was shown to ablate all stimulation-induced fMRI signals by the total blockage of peripheral nerve transmission, while the analgesic effect of systemically administered lidocaine was robustly detected after intravenous infusion of approximately 3mg/kg, which is similar to clinical dosage for human. This study establishes spinal cord fMRI as a viable assay for analgesics. With respect to the mode of action of lidocaine, this study suggests that systemic lidocaine, which is clinically used for the treatment of neuropathic pain, and believed to only block the peripheral nerve transmission of abnormal neural activity (ectopic discharge) originating from the damaged peripheral nerves, also blocks the peripheral nerve transmission of normal neural activity induced by transcutaneous noxious electrical stimulation.
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Clinical Trial
Thermal hyperalgesia as a marker of oxaliplatin neurotoxicity: a prospective quantified sensory assessment study.
Neurotoxicity represents a major complication of oxaliplatin. This study aimed to identify early clinical markers of oxaliplatin neurotoxicity, in comparison with cisplatin, and detect predictors of chronic neuropathy. Forty-eight patients with mainly colorectal cancer were evaluated prospectively before oxaliplatin (n=28) or cisplatin (n=20) administration and then 2 weeks after the third (C3), sixth (C6) and ninth (C9) cycles. ⋯ In contrast, thermal testing identified sustained (irreversible between cycles) neurotoxicity two weeks after C3 in the oxaliplatin group only, characterized by hyperalgesia to cold (5-25 degrees C) (F=11.4; p=0.0002 relative to cisplatin patient responses in the hand) and heat stimuli (38-48 degrees C) (F=4.1; p=0.049 for the hand). Cold-evoked symptoms lasting 4 days or more after C3 predicted chronic neuropathy (OR: 22; 95% CI: 1.54-314.74; p=0.02) whereas enhanced pain in response to cold (20 degrees C stimulus on the hand) predicted severe neuropathy (OR: 39; 95% CI: 1.8-817.8 p=0.02). Thermal hyperalgesia is a relevant clinical marker of early oxaliplatin neurotoxicity and may predict severe neuropathy.
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The involvement of TRPV1 and TRPA1 in mediating craniofacial muscle nociception and mechanical hyperalgesia was investigated in male Sprague-Dawley rats. First, we confirmed the expression of TRPV1 in masseter afferents in rat trigeminal ganglia (TG), and provided new data that TRPA1 is also expressed in primary afferents innervating masticatory muscles in double-labeling immunohistochemistry experiments. We then examined whether the activation of each TRP channel in the masseter muscle evokes acute nocifensive responses and leads to the development of masseter hypersensitivity to mechanical stimulation using the behavioral models that have been specifically designed and validated for the craniofacial system. ⋯ Similarly, pretreatment of the muscle with a selective TRPA1 antagonist, AP18, significantly blocked the MO-induced muscle nociception and mechanical hyperalgesia. We confirmed these data with another set of selective antagonist for TRPV1 and TRPA1, AMG9810 and HC030031, respectively. Collectively, these results provide compelling evidence that TRPV1 and TRPA1 can functionally contribute to muscle nociception and hyperalgesia, and suggest that TRP channels expressed in muscle afferents can engage in the development of pathologic muscle pain conditions.