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Review
. 2023;98(6):314-330.
doi: 10.1159/000535552. Epub 2023 Nov 30.

Exaptation and Evolutionary Adaptation in Nociceptor Mechanisms Driving Persistent Pain

Edgar T Walters  1
Affiliations
Review

Exaptation and Evolutionary Adaptation in Nociceptor Mechanisms Driving Persistent Pain

Edgar T Walters. Brain Behav Evol. 2023.

Abstract

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.

Keywords: Aplysia; Cyclic AMP signaling; Excitability; Mammals; Spontaneous activity.

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Conflict of interest statement

Conflict of Interest Statement

The author has no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
Two types of somal hyperactivity in nociceptors. a Afterdischarge generated by three kinds of peripheral stimulation delivered sequentially to the same Aplysia nociceptor in a semi-intact preparation with the tail attached to central ganglia containing the nociceptor somata: top panel, 0.5-s tap (75 g/mm2) to the neuron’s receptive field on the animal’s tail; middle panel, ~0.5-s pinch to the same receptive field; bottom panel, 0.25-s train of 2-ms shocks (20 Hz) to the nerve containing the nociceptor’s axon. The dashed purple line indicates the resting membrane potential (RMP) for comparison to the depolarizing afterpotential that can bring the soma membrane to action potential (AP) threshold. Afterdischarge when this potential is small, as shown here immediately after tail pinch, is generated peripheral to the soma, probably within the distant receptive field. The larger depolarizing afterpotential evoked in the soma by subsequent tail nerve shock triggers afterdischarge as a long-lasting consequence of the prior pinch. Modified from [51]. b Examples of RMP and one form of ongoing activity (OA) in nociceptors dissociated from dorsal root ganglia excised from a previously uninjured rat (left) and from a rat 2 months after spinal cord injury. Compared to the isolated control nociceptor shown on the left, the nociceptor from the previously injured rat exhibited OA at RMP (likely intrinsically generated spontaneous activity, SA), depolarization of RMP, enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential (MP), and decreased voltage threshold for AP initiation. The dashed purple line indicates RMP in the control nociceptor, and the dashed green line indicates AP threshold for each nociceptor. Modified from [52].
Fig. 2.
Fig. 2.
Core cAMP signaling modules described in Aplysia and rodent nociceptors that might have been exapted during early animal evolution to promote hyperactivity and persistent pain after bodily injury. a Scaffolded AC1-centered signaling implicated in the induction and possible maintenance of PNH in Aplysia. Some evidence suggests that AC1 signaling might also contribute to PNH in mouse Aδ nociceptors and possibly in Drosophila nociceptors (see text). The yellow elements are close orthologs in Aplysia and rodent nociceptors. It is not yet known whether other cAMP signaling elements (e.g., EPAC or HCN channels) function in Aplysia nociceptors. Most cAMP research on these neurons has focused on 5-HT stimulation, and the ion channels phosphorylated by PKA have not been identified, except for a TREK-1-like leak K+ channel inhibited by PKA. b AC5/6-associated signaling that contributes to the maintenance of PNH in rodent nociceptors. AC5/6 is also prominently expressed in Aplysia nociceptors, but their potential contribution to PNH in these neurons has not been explored. In rodents, numerous excitatory and inhibitory modulators and GPCRs can stimulate or inhibit AC5/6 in primary sensory neurons. AC5/6 is inhibited by Ca2+ and by opioids and other modulators coupled to Gi, and the Gi-mediated inhibition can be reduced by depolarization of RMP, at least in part through C-raf in the ERK pathway. Among the ion channels regulated by scaffolded PKA in these neurons are TRPV1, Nav1.8, Cav1.2, and KCNQ channels (not shown). Neither other scaffolded proteins such as phosphodiesterases and phosphatases nor pathways regulating DNA transcription and mRNA translation downstream from AC5/6 or ERK are shown. Activating effects are indicated by green arrows, inhibitory effects by red bars. 5-HT, serotonin; AC5, adenylyl cyclase 5; AC5/6, adenylyl cyclase 5 and/or AC6; AKAP150, A-kinase anchoring protein 150; AP, action potential; DSF, depolarizing spontaneous fluctuation; C, catalytic subunit of PKA; CaM, calmodulin; C-raf, Raf-1 proto-oncogene; cAMP, cyclic adenosine monophosphate; EPAC, exchange protein directly activated by cAMP; ERK, extracellular signal-related kinase; GPCR, G-protein-coupled receptor; Gi, inhibitory G-protein Gαi; Gs, stimulatory G-protein Gαs ; HCN, hyperpolarization-activated, cyclic nucleotide-gated channel; MEK, mitogen-activated protein kinase kinase; PKA, protein kinase A; RII; regulatory subunit II of PKA; Ras, “rat sarcoma virus” GTPase.
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References

    1. Rikard SM, Strahan AE, Schmit KM, Guy GP. Chronic Pain Among Adults - United States, 2019–2021. MMWR Morb Mortal Wkly Rep 2023; 72:379–385. - PMC - PubMed
    1. Gulliford M Opioid use, chronic pain and deprivation. EClinicalMedicine 2020; 21:100341. - PMC - PubMed
    1. Kuo YF, Baillargeon J, Raji MA. Overdose deaths from nonprescribed prescription opioids, heroin, and other synthetic opioids in Medicare beneficiaries. J Subst Abuse Treat 2021; 124:108282. - PMC - PubMed
    1. Williams ACC. What can evolutionary theory tell us about chronic pain. Pain 2016; 157:788–790. - PubMed
    1. Nesse RM, Schulkin J. An evolutionary medicine perspective on pain and its disorders. Philos Trans R Soc Lond B Biol Sci 2019; 374:20190288. - PMC - PubMed

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