In the not-so-distant past, it was standard clinical practice for newborn babies to undergo painful medical procedures without anaesthesia. This policy was based on the assumption that neonate mammals do not feel pain, an assumption that we now know to be incorrect. Not only can newborns feel pain, they are actually hypersensitive to mechanical stimuli — a characteristic so far thought to be mediated through the activation of low-threshold mechanoreceptors (LTMRs) in the skin. But a new study by Woodbury and Koerber challenges the LTMR-based hypothesis by providing evidence that a subset of high-threshold mechanoreceptors (HTMRs) with new morphology are instead responsible for the exaggerated pain reflexes of neonates.

Hypersensitivity to pain affects mice during the first 3 weeks of life. It has long been believed that LTMRs located in the skin possess extensive projections to superficial dorsal horn laminae — pain-specific regions of the spinal cord — and are therefore responsible for the perception of noxious stimuli during the hypersensitive period. According to the 'delayed maturity' hypothesis this 'inappropriate' projection of LTMRs into pain-specific areas undergoes gradual correction, so that by the third week of life LTMR projections adopt the more centralized pattern that characterizes adult anatomy, and hypersensitivity therefore subsides.

However, in a study published in 2001, Woodbury and colleagues showed that the delayed maturity scenario does not apply to LTMRs. The authors used an ex vivo somatosensory preparation to show that the LTMRs of neonatal mice are essentially miniaturized versions of their adult counterparts that do not project into pain-specific regions, and are therefore incapable of mediating the hypersensitive response. So, if LTMRs are not doing the job, what is?

In another study, published in The Journal of Neuroscience, Woodbury and Koerber turned their attention to HTMRs, an experimentally-neglected population of pain receptors. Using the same ex vivo preparation with skin and spinal cord in continuity, the authors identified two subsets of HTMRs, one of which gives rise to widespread projections throughout the entire dorsal horn laminae. So, this HTMR subset is ideally situated for the transduction of pain signals. In addition, electrophysiological data showed that the response of this HTMR population becomes increasingly vigorous as the intensity of painful stimuli increases — a physiological profile that makes these HTMRs ideally configured for warning against potential damage from noxious insults.

Interestingly, the postnatal development of HTMRs provides further justification for abandoning the delayed maturity hypothesis of mechanoreceptor development. As is the case for LTMRs, the neonatal phenotype of HTMRs matches that of their adult counterparts. If there are no notable alterations of the anatomy or physiology of the HTMR population, how is the hypersensitive response downregulated by the third week of life? The authors suggest that functional maturation of inhibitory inputs may confer the postnatal decrease in hypersensitivity, an idea that warrants further investigation as we rethink the mechanisms that regulate this intriguing developmental pathway.