Tendons such as the Achilles tendon are complex structures that are hypocellular, hypovascular, and hyponeural. The development of pathophysiologic function in this tendon because of overuse is relatively common; however, the mechanisms responsible for the development of paratenonitis and tendinosis remain primarily undefined. To understand better a possible regulatory role for neuropeptides (substance P and calcitonin gene related peptide) known to be present in this tissue, the influence of substance P and calcitonin gene related peptide on messenger ribonucleic acid levels for numerous inflammatory molecules, growth factors, and proteinases and inhibitors have been assessed using a semiquantitative reverse transcription-polymerase chain reaction method and explants of paratenon and Achilles tendon midsubstance tissue from adolescent male and female rabbits and tissue from primigravida females. Most of the significant (p < 0.01) changes observed were at the level of the growth factor transcripts and transcripts for proteinases and inhibitors. Twenty-one significant differences in the responsiveness between tissues from male and female rabbits were observed, and 12 significant differences in responsiveness between virgin females and primigravida rabbits were seen. Differences between paratenon and midsubstance responsiveness to the neuropeptides also were observed within each group of animals. The midsubstance tissue from pregnant animals was hyporesponsive to both neuropeptides. These results indicate that neurotransmitter responsiveness of Achilles tendon tissue differs in a gender specific manner and is influenced by pregnancy associated factors.