Nicotine stimulates expression of proteins implicated in peripheral and central sensitization

- Systemic administration of nicotine increased nocifensive behavioral response to mechanical stimulation in facial regions.
- Nicotine stimulated expression of p-ERK, p-JNK, PKA, GFAP, and Iba1 in the spinal trigeminal nucleus.
- Levels of several cytokines, including TNF, were significantly increased in the upper spinal cord by nicotine.
- Nicotine caused upregulation of p-ERK, p-JNK, and PKA expression in trigeminal ganglion neurons.
- Elevated levels of nicotine promote cellular changes associated with peripheral and central nociceptor sensitization.

Pain patients who are nicotine dependent report a significantly increased incidence and severity of pain intensity. The goal of this study was to determine the effects of prolonged nicotine administration on inflammatory proteins implicated in the development of peripheral and central sensitization of the trigeminal system. Behavioral, immunohistochemical, and microarray studies were utilized to investigate the effects of nicotine administered daily for 14 days via an Alzet® osmotic pump in Sprague Dawley rats. Systemic nicotine administration caused a significant increase in nocifensive withdrawals to mechanical stimulation of trigeminal neurons. Nicotine stimulated expression of the pro-inflammatory signal transduction proteins phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-c-Jun N-terminal kinase (p-JNK), and protein kinase A (PKA) in the spinal trigeminal nucleus. Nicotine also promoted elevations in the expression of glial fibrillary acidic protein (GFAP), a biomarker of activated astrocytes, and the microglia biomarker ionized calcium-binding adapter molecule 1 (Iba1). Similarly, levels of eleven cytokines were significantly elevated with the largest increase in expression of TNF-α. Levels of PKA, p-ERK, and p-JNK in trigeminal ganglion neurons were increased by nicotine. Our findings demonstrate that prolonged systemic administration of nicotine promotes sustained behavioral and cellular changes in the expression of key proteins in the spinal trigeminal nucleus and trigeminal ganglion implicated in the development and maintenance of peripheral and central sensitization.