Figure 3. Persistent nociceptor hyperactivity can be adaptive.

(A) Squid survival is enhanced by nociceptor activity after injury. Peripheral tissue injury causes long-lasting nociceptor hyperactivity expressed over much of the body surface [75] (red). In staged 30-minute encounters with fish predators [87], ~75% of uninjured subjects survived. Nearly half of squid previously receiving a minor arm amputation survived. Although selectively targeted by the fish, injured squid began their escape behavior farther from approaching fish (indicated by arrow length) than uninjured squid [87]. Squid that were injured without nociceptive sensitization and persistent nociceptor hyperactivity (prevented by transient block of nociceptor activity during amputation) waited longer to begin escape, with only ~20% surviving, indicating the survival benefit of persistent nociceptor hyperactivity after injury [86]. (B) Enhanced avoidance of a predator cue by mice with neuropathic pain. Mice with a spared nerve injury model exhibit nociceptor hyperactivity generated in the hindpaw (red) [138] and DRG [25,139] (not shown). When exposed to fox urine, injured mice chose a route that took them farther from the predator odor [88]. This suggests that injury-induced nociceptor hyperactivity promotes hypervigilance and increased risk aversion. (C) Speculative benefit of chronic nociceptor hyperactivity in ancestral humans at high risk for predation after injury (e.g., amputation injury in the illustration). The top two rows parallel the arguments for squid illustrated in panel A. The bottom row illustrates a situation of transient blockade of DRG APs in amputees that blocks ongoing pain [83]. If spontaneous activity in human nociceptors persistently drives hypervigilance as well as pain (as suggested by anxiety being a comorbidity of pain [90]), this hyperactivity should be protective for injured individuals who are more likely to be targeted by predators.