"Hormonal responses to needling show that there are functional brainstem and midbrain mediated reactions to noxious events but they, too, do not require higher brain processing to take place and can occur independently of sensory awareness. The specific relationship between pain and the release of hormones and neurotransmitters is unclear. In a prospective crossover study on 50 extremely low gestational age infants (less than 28 weeks of gestation), no difference in hormonal response was observed after heel lance15 and, in adult mice, it is difficult to distinguish changes in levels of naturally occurring opioids due to stressful handling from those due to tissue damage."