期刊
PAIN
卷 144, 期 3, 页码 253-261出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.pain.2009.03.027
关键词
Pain; Human; Clinical trial; Calcitonin gene-related peptide; TRPV1; MOR; Morphine; Capsaicin; Neuropeptide release; Translational studies; Analgesia; Exocytosis; Dental pulp; Sensory neuron
资金
- National Institutes of Health
- National Institute of Dental and Craniofacial Research [DE-015576, DE14318-06]
- National Institute of Neurological Disorders and Stroke [NS-58655, NS-45186]
- CTSA [U54RR02438]
- National Institute for Drug Abuse [DA-16719]
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. Informed consent was obtained from patients presenting for extraction of normal wisdom teeth. Patients were anesthetized using nerve block injection, teeth were extracted and bisected, and Pulp Was removed and superfused in vitro. Basal and capsaicin-evoked peripheral release of immunoreactive calcitonin gene-related peptide (iCGRP) was analyzed by enzyme immunoassay. The presence of nociceptive markets within neurons of the dental Pulp was characterized using confocal microscopy. Capsaicin increased the release of iCGRP from dental pulp biopsies in a concentration-dependent manner. Stimulated release was dependent on extracellular calcium, reversed by a TRPV1 receptor antagonist, and desensitized acutely (tachyphylaxis) and pharmacologically by pretreatment with capsaicin. Superfusion With phorbol 12-myristate 13-acetate (PMA) increased basal and stimulated release, whereas PGE(2) augmented only basal release. Compared with vehicle treatment, pretreatment with PGE(2) 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. Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
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