Pain
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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.
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Temporomandibular joint or related masticatory muscle pain represents the most common chronic orofacial pain condition. Patients frequently report this kind of pain after dental alterations in occlusion. However, lack of understanding of the mechanisms of occlusion-related temporomandibular joint and muscle pain prevents treating this problem successfully. ⋯ Removal of the crown 6 days after occlusal interference showed that the removal at this time could not terminate the 1 month duration of mechanical hyperalgesia in the masticatory muscles. Lastly, we systemically administered NMDA antagonist MK801 (0.2, 0.1, and 0.05 mg/kg) to the treated rats and found that MK801 dose dependently attenuated the occlusal interference-induced hyperalgesia. These findings suggest that occlusal interference is directly related to masticatory muscle pain, and that central sensitization mechanisms are involved in the maintenance of the occlusal interference-induced mechanical hyperalgesia.
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Spinal long-term potentiation (LTP) elicited by noxious stimulation enhances the responsiveness of dorsal horn nociceptive neurons to their normal input, and may represent a key mechanism of central sensitization by which acute pain could turn into a chronic pain state. This study investigated the electrophysiological and behavioral consequences of the interactions between LTP and descending oxytocinergic antinociceptive mechanisms mediated by the hypothalamic paraventricular nucleus (PVN). ⋯ In a behavioral model developed to study the effects of spinal LTP on mechanical withdrawal thresholds in freely moving rats, the long-lasting LTP-mediated mechanical hyperalgesia was transiently interrupted or prevented by either PVN stimulation or intrathecal OT. LTP mediates long-lasting pain hypersensitivity that is strongly modulated by endogenous hypothalamic oxytocinergic descending controls.
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The mechanisms underlying trigeminal pain conditions are incompletely understood. In vitro animal studies have elucidated various targets for pharmacological intervention; however, a lack of clinical models that allow evaluation of viable innervated human tissue has impeded successful translation of many preclinical findings into clinical therapeutics. Therefore, we developed and characterized an in vitro method that evaluates the responsiveness of isolated human nociceptors by measuring basal and stimulated release of neuropeptides from collected dental pulp biopsies. ⋯ Superfusion with phorbol 12-myristate 13-acetate (PMA) increased basal and stimulated release, whereas PGE2 augmented only basal release. Compared with vehicle treatment, pretreatment with PGE2 induced competence for DAMGO to inhibit capsaicin-stimulated iCGRP release, similar to observations in animal models where inflammatory mediators induce competence for opioid inhibition. These results indicate that the release of iCGRP from human dental pulp provides a novel tool to determine the effects of pharmacological compounds on human nociceptor sensitivity.