Background: Several evolutionary explanations have been proposed for why chronic pain is a major clinical problem. One is that some mechanisms important for driving chronic pain, while maladaptive for modern humans, were adaptive because they enhanced survival. Evidence is reviewed for persistent nociceptor hyperactivity (PNH), known to promote chronic pain in rodents and humans, being an evolutionarily adaptive response to significant bodily injury, and primitive molecular mechanisms related to cellular injury and stress being exapted (co-opted or repurposed) to drive PNH and consequent pain. Summary: PNH in a snail (Aplysia californica), squid (Doryteuthis pealeii), fruit fly (Drosophila melanogaster), mice, rats, and humans has been documented as long-lasting enhancement of action potential discharge evoked by peripheral stimuli, and in some of these species as persistent extrinsically driven ongoing activity and/or intrinsic spontaneous activity (OA and SA, respectively). In mammals, OA and SA are often initiated within the protected nociceptor soma long after an inducing injury. Generation of OA or SA in nociceptor somata may be very rare in invertebrates, but prolonged afterdischarge in nociceptor somata readily occurs in sensitized Aplysia. Evidence for the adaptiveness of injury-induced PNH has come from observations of decreased survival of injured squid exposed to predators when PNH is blocked, from plausible survival benefits of chronic sensitization after severe injuries such as amputation, and from the functional coherence and intricacy of mammalian PNH mechanisms. Major contributions of cAMP-PKA signaling (with associated calcium signaling) to the maintenance of PNH both in mammals and molluscs suggest that this ancient stress signaling system was exapted early during the evolution of nociceptors to drive hyperactivity following bodily injury. Vertebrates have retained core cAMP-PKA signaling modules for PNH while adding new extracellular modulators (e.g., opioids) and cAMP-regulated ion channels (e.g., TRPV1 and Nav1.8 channels). Key Messages: Evidence from multiple phyla indicates that PNH is a physiological adaptation that decreases the risk of attacks on injured animals. Core cAMP-PKA signaling modules make major contributions to the maintenance of PNH in molluscs and mammals. This conserved signaling has been linked to ancient cellular responses to stress, which may have been exapted in early nociceptors to drive protective hyperactivity that can persist while bodily functions recover after significant injury.

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