Alpha 2-adrenergic receptor activation inhibits calcitonin gene-related peptide expression in cultured dorsal root ganglia neurons.

Calcitonin gene-related peptide (CGRP), a potent vasodilator, is produced in dorsal root ganglia (DRG) neurons which extend nerves peripherally to blood vessels and centrally to the spinal cord. We previously reported that neuronal CGRP expression is significantly reduced in the spontaneously hypertensive rat (SHR) which could contribute to the elevated BP. Other studies suggest that the enhanced activity of the sympathetic nervous system in the SHR may mediate, at least in part, this reduction in neuronal CGRP expression via activation of alpha 2-adrenoreceptors (alpha 2-AR) on DRG neurons. To test this hypothesis in vitro we employed primary cultures of adult rat DRG neurons. Neuronal cultures were initially exposed (24 h) to either the alpha 2-AR agonist UK 14,304 (10(-6) M) or vehicle; however, no changes in CGRP mRNA content or immunoreactive CGRP (iCGRP) release were observed. Using the rationale that in vivo DRG neurons receive a continuous supply of target tissue derived nerve growth factor (NGF), which stimulates CGRP synthesis, the cultured neurons were treated (24 h) with either vehicle, NGF (25 ng/ml) alone, or NGF plus UK. NGF treatment increased CGRP mRNA accumulation 5.5 +/- 0.9-fold (p < 0.001) and iCGRP release 2.9 +/- 0.4-fold (p < 0.001) over control levels. The stimulatory effects of NGF were markedly attenuated, but not abolished, by UK (NGF + UK vs. control, CGRP mRNA, 2.9 +/- 0.4-fold, p < 0.05; iCGRP, 1.7 +/- 0.2-fold, p < 0.05). These values were also significant (p < 0.05) when compared to NGF treatment alone. Experiments performed using the alpha 2-antagonist yohimbine confirmed that the effects of UK were mediated by the alpha 2-AR. These results, therefore, demonstrate that alpha 2-AR activation attenuates the stimulatory effects of NGF on CGRP expression in DRG neurons.