Pain sensitivity: Associated with Neanderthal genes and autism?

Article by: Emil Koch, on 24 October 2023, at 12:34 CEST

What makes some people more sensitive to pain than others? With age, pain sensitivity seems to increase on average, and women are considered "pain sensitive." But despite these observations, the molecular mechanism had been obscure for long.

A recent study conducted by a team of researchers at UCL has unveiled that individuals inheriting three specific Neanderthal genes exhibit heightened sensitivity to particular forms of pain. Before this work, the exact sensory responses were unclear, while the Neanderthaler variants M932L, V991L, and D1908G of the sodium voltage-gated channel SCN9A had been linked to greater pain sensitivity. This sodium channel is highly expressed in sensory neurons and crucial for actional potential generation. Importantly, SCN9A, also called Nav1.7, amplifies very small depolarizations and especially acts in the early phases of neuronal electrogenesis.

The researchers' findings uncovered the existence of the D1908G, M932L, and V991L genetic variants, with a prevalence of 20% in the first group and 30% in the latter two, within a study population comprising 1,963 individuals from Colombia. Notable variations were observed in skin sensitivity following previous exposure to mustard oil, yet no significant differences were detected in response to heat or pressure. Furthermore, the combined presence of all three genes had a cumulative impact on pain sensitivity, meaning all three genes conferred more pain sensitivity than one gene alone. Of note, the authors further discovered a higher prevalence of Neanderthal variants in populations with higher proportions of Native American ancestry when comparing data from 5,971 people from Brazil, Chile, Colombia, Mexico, and Peru.

They speculate about a possible ecological advantage higher pain sensitivity might have given in terms of chances of survival, evolutionary speaking. Put differently, Neanderthalers might have been more pain-sensitive in some regards; nevertheless, they caution that pain involves multi-faceted factors, including psychological and environmental factors. Now, while differential pain sensitivity might not be new and partially explained by chronic neuropathic pain as a result of microglia dysregulation with age, as suggested by Yezierski (2012), there is an intriguing connection between a rare missense variant of SCN9A and familial autism (Rubinstein et al., 2018). Genetic factors, amongst other things, are thought to account for sex differences in pain perception to some degree (Hashmi et al., 2014). Considering that mounting evidence substantiates increased pain (Failla et al., 2020) and generally tactile sensitivity (Asmika et al., 2018; Blakemore et al., 2006), the question arises whether the autism spectrum disorders (ASD) are an artifact of Neanderthals. Some evidence supports this view. For example, the AUTS2 gene is a high-confidence autism gene, according to the Simons Foundation Autism Research Initiative (SFARI), and is among the genes most significantly positively selected throughout human evolution (Oksenberg et al., 2013). Another example is FOXP2, involved in speech development inks between Neanderthals and autism are observable (Benítez‐Burraco et al., 2016).

In conclusion, pain sensitivity might involve a genetic profile rooted back to Neanderthals that possibly brought evolutionary fitness through avoiding painful things that might bring harm but may also extend to complex traits like autism. This suggests that genetic legacies from our Neanderthal relatives could have far-reaching implications in understanding not only our pain perception but also neurodevelopmental disorders.

References:

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