Drug-induced oral ulcers are lesions of the oral mucosa accompanied by painful symptoms, such as burning mouth, metallic taste, dysgeusia, or ageusia. This report demonstrates the first documented case of drug-induced oral ulcers with the tricyclic antidepressant nortriptyline. In this case, a 49-year-old female initiated treatment for refractory neuropathy with nortriptyline. Within 2 weeks of therapy, painful, oral, bubble-like ulcers developed. Complete symptom resolution occurred approximately 1 month after discontinuation of nortriptyline. Clinicians should be cognizant of nortriptyline's ability to potentially induce oral ulcers; however, the exact mechanism for this adverse event is unknown.

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP-expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP-positive populations using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP-positive small peptidergic sensory neurons (calcitonin gene-related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP-positive free nerve endings in the skin. These changes were not present in nerve-injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine-treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing.