Impact of chronic nicotine on the development and maintenance of neuropathic hypersensitivity in the rat

Rationale Clinical data support a correlation between smoking and the incidence and severity of some chronic pain conditions. However, the impact of nicotine on neuropathic pain has been largely ignored in the laboratory setting.Objectives The purpose of these studies was to determine if chronic nicotine would alter mechanical hypersensitivity after spinal nerve ligation.Materials and methods Rats were implanted with osmotic mini pumps to administer either saline or nicotine (4, 10, or 24 mg/kg/day) for 7 or 21 days. On day 7 of saline/nicotine administration, rats receiving 24 mg/kg/day nicotine underwent spinal nerve ligation. Mechanical thresholds to pressure were measured across nicotine exposure and spinal cords were collected on days 7 or 21. Spinal cord slices were immunostained for phosphorylation of cAMP response element binding protein (pCREB), to determine general neuronal activity, and for cleaved caspase-3, as a marker for apoptosis.Results Chronic nicotine produced a dose-dependent and stable mechanical hypersensitivity, which could be blocked with the α4β2-selective antagonist, dihydro-β-erythroidine (DHβE). Spinal nerve ligation also produced a stable mechanical hypersensitivity, which was exacerbated in the presence of chronic nicotine. Differences in mechanical sensitivity were reflected in spinal pCREB, which was highly correlated with the degree of mechanical hypersensitivity. Chronic nicotine also altered the number of pro-apoptotic cells in the spinal cord as measured by cleaved caspase-3.Conclusions These findings demonstrate that chronic nicotine produces a stable, long-lasting, mechanical hypersensitivity that exacerbates mechanical sensitivity resulting from peripheral nerve injury. The mechanism of this may involve an increase in spinal neuronal activity and apoptosis.