Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury

Abstract

Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.

1. Clinically maladaptive pain need not be evolutionarily maladaptive

The concept of maladaptive pain has become increasingly important for biomedical investigators and clinicians. Unlike many definitions of pain in use by clinically oriented experts, maladaptive pain is defined functionally rather than by symptomatic or mechanistic features. Typically, maladaptive pain is defined as dysfunctional pain that ‘neither protects nor supports healing and repair’ [1]. Maladaptive pain encompasses numerous types of pain, including peripheral and central neuropathic pain, fibromyalgia, irritable bowel syndrome, interstitial cystitis and inherited pain disorders such as paroxysmal extreme pain disorder. While maladaptive pain has diverse causes, virtually all forms are chronic (lasting from three months to a lifetime) and are highly resistant to treatment. At least some forms of maladaptive pain are now considered diseases in their own right, caused by prolonged or permanent malfunction of the somatosensory system [1–4].

From a clinical point of view, maladaptive pain has no function and does not benefit the sufferer. Moreover, experts in evolutionary medicine have suggested that, as a dysregulation of adaptive somatosensory physiology, chronic pain can either reduce reproductive success (decreasing Darwinian fitness) or be adaptively neutral if it occurs (as it often does) following the reproductive phase of life [5,6]. However, a lack of any clinical benefits of chronic pain does not mean that some forms of pain that seem maladaptive for modern humans did not enhance the survival and reproductive success of our ancestors. I will argue that at least one relatively common natural scenario has favoured the selection of mechanisms that make humans prone to chronic pain, and I will explain how common features of nociceptive sensory neurons that in humans are very important for driving persistent pain are consistent with this evolutionary hypothesis.

2. Increased vulnerability after severe injury is a plausible selection pressure for the evolution of mechanisms important for chronic pain

When predators first appeared, well over half a billion years ago, animals began to be injured not only by non-biological causes, such as wave action, but also by attacks from predators and aggressive, sometimes well-armed conspecifics [7,8]. At least since Darwin, biologists have recognized predation as a leading cause of animal mortality and shaper of defensive adaptations [7,9]. Interestingly, attacks by most predators are usually unsuccessful and often leave prey with sublethal but serious injuries [7]. Predators also can sustain injuries when attacking prey [10], further increasing the incidence of predation-related injury. An injured animal becomes much more vulnerable to attack by predators, which often preferentially target prey exhibiting signs of injury or illness [11–16]. Importantly, numerous anecdotal observations indicate that many animals, including large mammals, can survive horrific, disabling injuries such as amputations of major limbs [17], and sometimes reproduce after disfiguring injury (e.g. [18,19]). For example, cases have been described in which wild hyenas raised cubs successfully after amputation or disabling fractures of both hindlimbs; remarkably, after being mauled by other hyenas, one female hyena survived as a paraplegic for at least 9 years [19]. In addition, there is substantial evidence in the fossil record for healing after serious injury, for example, in trilobites [20] and dinosaurs [21,22]. Together, these observations suggest effective selection during evolution for adaptive responses to severe, persistent injuries.

One plausible adaptive response to severe injury (figure 1) is to increase vigilance during the period of heightened vulnerability so that detection of threats and production of appropriate defensive behaviour can be made as early as possible [17]. This hypothesis was supported by our showing that partial amputation of one arm of a squid increased vigilance for as long as was tested after the injury (2 days), with the hypervigilance indicated by sensitization of defensive responses to visual stimuli and weak cutaneous stimuli [23], and possibly by sensitization of nociceptor responses to noxious cutaneous stimuli [24]. Blocking the induction of amputation-induced hypervigilance in squid significantly reduced survival during staged attacks by a natural fish predator, providing the first demonstration that injury-induced hypervigilance increases fitness [11]. The increased sensitivity to mechanical stimuli is functionally similar to allodynia (pain-like responses to innocuous stimuli) and the increased sensitivity to visual stimuli appears functionally similar to anxiety, a very common comorbidity of pain in humans and other mammals [17,23–26]. Enhanced responsiveness of nociceptors after injury in squid suggests that the functional equivalent of hyperalgesia (enhancement of pain-like responses to noxious stimuli) may also occur in this mollusc [24], as had been found in the marine snail Aplysia californica [27,28]. A severe injury that produces disability or abnormal movement (as often occurs after limb amputation) attracts the attention of other animals, and it may permanently increase vulnerability to attacks by predators and aggressive conspecifics. Under such conditions, chronic hypervigilance and caution in behavioural activities may be adaptive, despite the biological costs resulting from an increase in defensive behaviour taking attention, energy and time from other behaviour essential for fitness, such as foraging and reproductive activities (figure 1).

Figure 1.

How persistent ongoing activity in nociceptors following severe bodily injury could increase evolutionary fitness by reducing heightened vulnerability to attack, despite the costs of continuing hypervigilance (e.g. from lost opportunities to forage and mate). Two streams of consequences of severe injury are shown; the upper stream (blue arrows) highlights some of the consequences that decrease fitness, while the lower stream (red arrows) highlights pain-related effects that can increase fitness. Successful host defence, repair and regeneration normally reduce the production of injury and inflammation signals, eventually decreasing ongoing activity in nociceptors and its consequences. (Online version in colour.)

In injuries permitting sufficient repair to allow effective recuperation and restoration of normal movements, it should be adaptive for a recovering animal to continuously receive sensory information about the physiological status of an injured body part, permitting the animal to discontinue biologically costly hypervigilant behaviour when no longer needed. Severe injuries introduce a major problem for such physiological monitoring though; sensory pathways to severely damaged tissue are likely to be disconnected traumatically from the central nervous system (CNS). Moreover, natural injuries are messy—unlike the precise surgical injuries performed clinically or used experimentally to study nerve regeneration in animal models—leaving tortuous paths through fibrotic tissue that can prevent reinnervation of the disconnected tissue. In the case of amputation, much of the damaged tissue is completely lost. When the severity of an injury is sufficient to prevent adequate sensory reinnervation of damaged body parts, how does a recovering animal know if and when it is safe to cease hypervigilance? One answer is in what often are considered ‘dysregulated’ or ‘dysfunctional’ properties of primary nociceptors that promote chronic pain.

3. Chronic ongoing electrical activity in primary nociceptors may reduce vulnerability after severe injury

Continuing activity from inflammation-detecting sensory neurons can inform the CNS that effective healing has not occurred in injured tissue (figure 1). Conversely, one way in which the CNS could be informed of adequate healing of damaged peripheral tissue is for ongoing sensory discharge stimulated by injury-induced inflammation to abate when the inflammation resolves (figure 1). In mammals, inflammation is detected locally by subsets of primary nociceptors [29,30]. Nociceptors are defined by their preferential activation by stimuli that produce tissue damage (or would do so if a noxious stimulus is sufficiently prolonged) [31]. Nociceptors have been described in diverse taxa, and display apparent specializations to match properties of the tissue innervated and each species' lifestyle [17,32] (see [33]). Nociceptors normally are electrically silent (figure 2a) unless activated by a noxious peripheral stimulus, such as dangerous pressure, heat or cold. Spontaneous or ongoing activity that persists longer than a few seconds is uncommon in nociceptors, with the notable exception of subsets of mammalian nociceptors that discharge continuously (spontaneously) during inflammation [34–37]. In principle, the number of nociceptors with ongoing activity and the degree of their activity could be integrated by the CNS to estimate the severity of injury, the extent of healing and, implicitly, the degree to which an animal's vulnerability to attack is increased by the injury. Consistent with this functional hypothesis is strong evidence that continuing electrical activity generated by primary afferent neurons (which include nociceptors) is important for maintaining chronic pain associated with peripheral nerve injury in humans. The evidence in both humans [38,39] and rodents (e.g. [40,41]) was that peripheral injection of a local anaesthetic such as lidocaine that blocked action potential conduction from the painful region often reversed pain (self-reported pain in humans, or pain-related hypersensitivity of withdrawal responses or hyperactivity in spinal cord neurons of rodents).

Figure 2.

Functional specializations that promote persistent ongoing activity and enhanced evoked activity in nociceptors following severe bodily injury. (a) Under normal conditions, nociceptors are silent unless a noxious stimulus is received by peripheral terminals. No action potentials (APs) are generated without such stimulation because the resting membrane potential (RMP) is strongly hyperpolarized relative to threshold, and the gap cannot be bridged by spontaneous depolarizations (DSFs). (b) After severe bodily injury, intrinsic alterations and extrinsic chemical signals promote ongoing activity (and enhance evoked activity) in numerous injured and nearby uninjured nociceptors by multiple mechanisms. RMP depolarizes and AP threshold hyperpolarizes, narrowing the gap for ongoing or evoked generation of APs. Irregular DSFs are greatly enhanced, some becoming large enough to reach the depressed AP threshold and generate low-frequency, random discharge. This discharge can continue during sustained depolarization of RMP because of the unusual resistance of Nav1.8 channels to voltage-dependent inactivation. Increased expression of receptors for damage-related molecular signals (e.g. ATP) and inflammation-related signals (cytokines, growth factors) allows circulating chemical signals to enhance the generation of ongoing activity in different parts of the nociceptor. Ongoing and enhanced evoked activity in nociceptors drive central pathways that result in ongoing pain and hypervigilance (anxiety and hypersensitivity to innocuous and noxious stimuli). (Online version in colour.)

Severe injuries such as amputation transect major nerves and thus would be expected to induce ongoing activity in some primary sensory neurons just as other nerve injuries do. In humans, only part of amputation pain is reversed by peripheral nerve block [42,43], a finding that encouraged the hypothesis that phantom limb pain is produced primarily by prominent alterations that have been observed within the CNS rather than by alterations within peripheral sensory neurons [44]. However, it was found that lidocaine delivered into the intraforaminal space of human amputees to selectively block activity in the contained dorsal root ganglion (DRG) produced a dramatic reversal of phantom limb pain [45]. The DRG houses the cell bodies of primary afferents, which would not have been affected directly by the peripheral lidocaine injections used in previous studies of amputation pain. Furthermore, this study showed that ongoing phantom limb pain was reversed by a low dose of intraforaminal lidocaine that failed to block stump pain in the amputees but is known to block ongoing (as opposed to evoked) activity in primary afferents [46]. These results indicate that a major driver of ongoing phantom limb pain, and perhaps secondarily of some of the central neural alterations associated with amputation, is ongoing activity generated in the cell bodies of sensory neurons in DRGs connected to the stump of an amputated limb [45]. Activity generated in the sensory neuron cell body (soma, figure 2a) is considered ‘ectopic’ because it is generated away from the normal generation site in the peripheral terminals. As will be discussed in the next section, ectopic activity generated at this site does not have to be maladaptive.

What types of sensory neuron drive ongoing pain after severe peripheral injury? The lidocaine injections in the studies just described would have prevented action potential generation in all of the many types of primary somatosensory neuron. Three lines of evidence suggest that primary nociceptors are particularly important for driving ongoing pain. First, in human volunteers, phasic or tonic stimulation of small numbers of unmyelinated C-fibre or Aδ-fibre nociceptors (which were recorded at the time of stimulation using microneurographic methods) was found to be necessary and sufficient to evoke conscious pain by nerve stimulation [47,48], whereas stimulation of large, non-nociceptive, Aβ fibres failed to produce pain [49]. This implies that, after severe injury (e.g. [40,41]), ongoing activity (often referred to as spontaneous activity) in nociceptors should produce ongoing pain. Second, long-lasting ongoing activity in C-fibre nociceptors occurs in rodent pain models that involve nerve injury and inflammation [34,50–52]. Third, ongoing activity in nociceptors, including many mechanically insensitive, ‘silent’ C-fibres, is highly correlated with ongoing pain in humans [53,54] and with experimental indicators of ongoing pain—notably, guarding behaviour and conditioned preference for a place associated with relief of ongoing pain—in rodent models of neuropathic, inflammatory and post-operative pain [34,55,56]. In a rat model of neuropathic pain produced by spinal cord injury, nociceptors display chronic hyperexcitability and ongoing/spontaneous activity [37,57–60]. Importantly, ongoing pain after spinal cord injury was reversed by knocking down the protein expression of a voltage-gated Na⁺ channel, Nav1.8, that is expressed selectively in primary somatosensory neurons (including more than 90% of nociceptors [61]), and which is necessary for ongoing activity in nociceptors [62]. Thus, strong evidence indicates that ongoing or spontaneous activity in mammalian nociceptors can drive ongoing pain after injuries severe enough to cause major neural damage and associated inflammation. Persistent ongoing activity could inform the CNS of long-lasting impairment of bodily function and thereby indicate increased vulnerability to predators and aggressive conspecifics (figure 1).

4. Complex physiological and anatomical specializations promote persistent ongoing activity in nociceptors following severe injury

Primary nociceptors in mammals exhibit several unusual specializations that enable them to generate adaptive hyperactivity for long periods, even after traumatic disconnection from their receptive fields. Some specializations overcome biological obstacles that oppose the continuous generation of ongoing activity that can faithfully represent the status of severely damaged tissue over periods of days to decades. One obstacle is that, until healing occurs (typically over weeks to months for major injuries), conditions in injured and inflamed tissue are highly depolarizing, which causes steady-state inactivation of voltage-gated Na⁺ channels and other cellular effects that depress excitability and can prevent discharge of action potentials. A unique specialization of mammalian nociceptors for action potential generation is a reliance on Nav1.8 channels, which require substantially more depolarization to inactivate and activate than do other Nav channels (e.g. [63]). These properties help to prevent both sustained inactivation and transient overactivation (which would cause activity-dependent inactivation) of a nociceptor so that ongoing discharge during persistent depolarization can continue (figure 2b).

A second, newly recognized electrophysiological specialization of nociceptors is a dependence on irregular, low-frequency, depolarizing spontaneous fluctuations (DSFs) of membrane potential to control ongoing activity (figure 2b). In the absence of transient depolarizing inputs (typically, noxious mechanical stimuli) to the peripheral terminals of nociceptors, DSFs can bridge the gap between the resting membrane potential and the voltage threshold for action potential generation. This means that in response to prolonged, moderate depolarization produced by damage-associated molecules (e.g. K⁺, H⁺, ATP) or inflammatory agents (e.g. cytokines, bradykinin, prostaglandins, serotonin; see [64]), action potentials are initiated by infrequent large DSFs that reach threshold rather than by sustained suprathreshold depolarization, allowing the Na⁺ channels to recover from inactivation and ongoing activity to continue. After severe injury and inflammation, ongoing activity in nociceptors is enabled by all three of the general electrophysiological alterations that, in principle, can promote sustained activity in the absence of brief excitatory inputs: (i) depolarization of the resting membrane potential, (ii) reduction (hyperpolarization) of action potential threshold, and (iii) enhancement of DSF amplitude, making it likely that DSFs will sometimes bridge the gap between the resting membrane potential and action potential threshold (figure 2b). This was first shown in a study of rat spinal cord injury [37], but the same three fundamental alterations have now been found in nociceptors dissociated from rats and mice suffering from other neuropathic conditions (A. G. Bavencoffe, S. C. Berkey, M. A. Odem, C. W. Dessauer, A. Kavelaars, E. T. Walters 2018–2019, unpublished observations) and from DRGs innervating painful regions of human patients with compression injuries of spinal nerves and roots [65] (R. Y. North, M. A. Odem, Y. Li, M. Patel, S. S. Cheruvu, A. G. Bavencoffe, E. T. Walters, P. M. Dougherty 2019, unpublished observations). While ongoing activity in nociceptors can be promoted by extrinsic chemical inputs, as discussed below, the ongoing activity depends upon alterations that are intrinsic to the nociceptor, with ongoing activity sometimes occurring spontaneously in these normally silent neurons without apparent extrinsic input under conditions of near isolation [37]. The comprehensive set of alterations underlying ongoing activity strongly implies that these are not unrelated features but are instead coordinated adaptive specializations for sustained, low-frequency, irregular activity. The low frequency and irregularity of firing may be useful for preventing not only activity-dependent depression of excitability in each nociceptor, but also in preventing overexcitation of downstream neurons in the spinal dorsal horn that receive convergent input from the large number of nociceptors that would be persistently activated by severe injury and inflammation [17]. Thus, this optimized mode of nociceptor activation can provide continuing information about injured body regions without producing excessive activity that could silence critical initial or downstream links in pain pathways by homeostatic reactions or frank excitotoxicity.

A third nociceptor specialization for continuing activity during substantial injury and inflammation is expression (both constitutive and inducible) of relevant receptors in parts of the nociceptor outside the peripheral receptive field. This is adaptive because it permits continuing activation by inflammatory signals of primary nociceptors that represent tissue that has been severely damaged, even if the peripheral terminals of the nociceptors have been disconnected (permanently or reversibly) from the soma and CNS by the injury. The activation of a nociceptor by prolonged exposure to chemical signals may occur in uninjured peripheral terminals, but also at three other sites (figure 2a), which will remain even after traumatic disconnection from peripheral terminals: (i) at the proximal stump of the severed axon within a neuroma [66,67], (ii) along the uninjured parts of the axon [68–70], and (iii) in the soma within the sensory ganglion (and also after dissociation) [50,58,71,72]. The unusual location in vivo of nociceptor (and other DRG neuron) somata within the intrathecal space under the vertebrae not only protects the somata from peripheral injuries, but also permits each soma to directly monitor systemic indicators of severe bodily injury. DRG neuron somata are exposed to humoural signals (figure 3) both in the cerebrospinal fluid, which bathes all the sensory ganglia, and in the blood, because the ganglia lack an effective vascular permeability barrier [73,74]. Post-translational modifications [30] and increased expression of receptors for various injury- and/or inflammation-related signals in the somata of nociceptors after neural injury or inflammation can further increase the sensitivity of all parts of the nociceptor to these signals. In addition, inducible expression of receptors for persistent injury signals (e.g. [75,76]) may permit silent, mechanically insensitive nociceptors to develop ongoing activity. Notable receptors linked to pain and reported to be upregulated in the somata of probable nociceptors in injury- or inflammation-related conditions include TrkA and TrkB [77], bradykinin receptor B2 [78], TRPV1 [59,79–81], TRPA1 and TRPM8 [82,83], ASIC3 channels [84], P2X₃ receptors [85], GluA1 and mGluR1 receptor subunits [86], the damage-associated molecular pattern, RAGE [87] and the pathogen-associated molecular pattern, TLR4 [88]. Humoural injury and inflammation signals (figure 3) may also act on nociceptors via satellite glial cells in the DRG [89,90] or inflammatory cells such as macrophages that release substances such as reactive oxygen species to excite or sensitize sensory neuron terminals or somata [91–93]. Receptors that can directly or indirectly excite or sensitize nociceptors are stimulated by numerous molecules used clinically as biomarkers of bodily injury and inflammation because of their release into the blood and/or cerebrospinal fluid [94–97]. Although the concentrations of circulating chemical signals of injury and inflammation are low (e.g. [98]), in appropriate combinations, their additive or synergistic effects on nociceptors that have become both hyperexcitable and hypersensitive to injury and inflammation signals (figure 2b) are likely to add to ongoing activity in a substantial number of nociceptors. Ongoing activity in the nociceptor soma may also be promoted by increased expression of at least one ion channel required for this activity, Nav1.8, which can increase expression in response to inflammatory signals [62,99–102]. Thus, long-lasting intrinsic alterations can be integrated with continuing extrinsic inputs after serious bodily injury [103] to generate ongoing activity in hypersensitive, hyperexcitable nociceptors, serving to continuously inform a seriously injured animal that it remains highly vulnerable (figure 1). These intrinsic and extrinsic alterations after bodily injury will also sensitize nociceptors, contributing to hyperalgesia (figure 2b) (e.g. [37,104]), and might also occur in low-threshold mechanoreceptor neurons (figure 3), contributing to allodynia [105], with the resulting hypersensitivity enhancing defensive hypervigilance [17].

Figure 3.

Functional specializations that enable the modulation of sensory neurons by humoural signals of injury and inflammation to promote ongoing pain and hypervigilance after severe bodily injury. The site of injury is not shown; it could be peripheral (e.g. an amputation) or peripheral and central (e.g. spinal cord injury). Blood-borne signals would also modulate sensory terminals and axons near the site of injury, especially if the injury disrupts the blood–nerve barrier (not shown). Blood-borne signals include chemicals such as cytokines, biogenic amines, growth factors and damage-associated molecular patterns (DAMPs), plus inflammatory cells such as macrophages (M) that infiltrate into the DRG as well as the site of injury. Access to the DRG is promoted by the absence of an effective vascular permeability barrier. Chemical signals diffusing from the blood or released from macrophages (such as reactive oxygen species) might act on any of the cells in the DRG, including the somata of nociceptors (both C-fibre and thinly myelinated Aδ-fibre—not shown), myelinated low-threshold mechanoreceptors, and satellite glial cells (SGC). After either peripheral or central injury, chemical signals (e.g. cytokines, neuromodulators, DAMPs) released into the cerebrospinal fluid (CSF) from cells in the CNS have direct access to cells in the DRG because of the ganglion's location within the intrathecal space. (Online version in colour.)

5. Strong arguments for the evolutionary adaptiveness of persistent ongoing activity in nociceptors have clinical implications

I have offered functional arguments to explain why a set of complementary mechanisms in mammalian nociceptors enable these neurons to continuously drive ongoing pain after severe bodily injury. I also have argued that these mechanisms can promote survival and thereby increase evolutionary fitness even though they produce clinically maladaptive suffering in the modern world. A compelling hypothesis about the adaptiveness of any trait—such as the intricate set of mechanisms that promotes persistent ongoing activity in nociceptors after bodily injury—demands strong arguments based on empirical evidence. Evolutionary biologists rightly dismiss ‘just-so stories’ of adaptations that do not meet accepted scientific criteria. Stearns & Medzhitov [6] have listed four empirical criteria for recognizing evolutionary adaptations. The first—to observe natural selection of the trait across generations—is not germane because it cannot be applied to a complex mammalian trait that already has evolved. The second is to perturb the trait experimentally and observe a change in Darwinian fitness. This has not been done with mammalian nociceptors, but as mentioned above, an experimental manipulation that blocked injury-induced ongoing activity in squid nociceptors reduced survival during staged encounters with a natural predator [11]. Although we do not know the cellular mechanisms underlying injury-induced ongoing activity in squid nociceptors, and they might differ from those in mammalian nociceptors, this finding indicates that injury-induced ongoing activity in nociceptors can be adaptive. In principle, similar information might be obtained from natural perturbations analogous to the morbid congenital insensitivity to pain associated with very rare mutations of genes linked to nociceptor function [106,107], but mutations that selectively perturb persistent ongoing activity in nociceptors have yet to be looked for. The third criterion is to show that the trait increases its expression in response to functional demand. As described above, this is evident in the persistent increases in ongoing nociceptor activity that have been documented after multiple forms of bodily injury and inflammation, and the association of this hyperactivity with increased molecular expression of relevant receptors and with appropriate changes in expression of ion channels to promote ongoing activity. Fourth is the ‘design criterion’, which states that natural selection for a trait ‘is more likely if the trait is precise and complex, conforming to a priori design principles' [6] (see also [108]). The effective evolutionary ‘design’ is indicated here by ongoing activity in nociceptors being promoted simultaneously by all three of the logically possible electrophysiological alterations that can produce ongoing activity in the absence of transient depolarizing inputs: depolarized resting membrane potential, reduced action potential threshold and enhanced spontaneous depolarizations (DSFs). Each of these electrophysiological responses to bodily injury involves complex cellular mechanisms. These mechanisms are complemented by physiological specializations (including distinctive properties of Nav1.8 channels) and anatomical specializations (the protected location and lack of a vascular permeability barrier for sensory ganglia) that allow the soma as well as the axon and peripheral terminals of nociceptors to generate ongoing activity after injury (figure 2b), and to be stimulated by diverse chemical signals of injury and inflammation coming from both the blood and cerebrospinal fluid (figure 3). These functionally consistent features strongly imply integrated adaptations for promoting persistent ongoing activity in nociceptors after severe injury.

A plausible evolutionary selection pressure may have helped shape this complex adaptation for persistently promoting pain. Living in a world where predation upon humans by other species is almost non-existent, we forget that, over periods of many hundreds of million years, predation was a leading cause of mortality and morbidity for most of our ancestors. Violent competition among conspecifics also was common for many of our ancestors. What has not been considered in discussions of possible functions of persistent pain is the information such pain can provide to the sufferer about her or his continuing vulnerability to threats resulting from injury severe enough to persistently impair normal motor function. An individual who maintains hypervigilance because of painful ongoing activity representing a mangled body part is less likely to get close to a predator or competitor that would preferentially target the individual because of the individual's evident disability. Despite the biological costs of prolonged hypervigilance, anecdotal evidence from mammalian species suggests that continuing hypervigilance can increase survival long enough to allow a severely injured animal to reproduce. This would allow positive selection of mechanisms that persistently maintain painful, anxious awareness of disability. Nociceptors are well positioned both to drive ongoing pain matched to the severity of an injury and to monitor local and systemic signs of recovery so that the ongoing activity promoting pain and anxiety (hypervigilance) can be terminated when no longer needed. With very severe injuries, the costs of erroneously deciding that adequate recovery has occurred (a false conclusion of normalized vulnerability, which would result in increased risk of being attacked) may outweigh the energy costs of unnecessarily maintaining hypervigilance after adequate recovery. Thus, the ‘smoke alarm principle’ [5] (see also [109]) may bias nociceptors after severe injury, so that residual signals of disability can outweigh signals of recovery, resulting in chronic pain and anxiety continuing after vulnerability has returned to normal.

These arguments have clinical implications. For example, defining maladaptive pain as pain that has no protective function is probably correct only for people living in the modern era with access to medical care and who are not threatened either by large predators or by aggressive humans who might selectively attack the physically impaired. In many natural contexts, persistent ongoing pain and ‘comorbid’ anxiety following injuries severe enough to cause long-lasting motor impairment are likely to reduce mortality after injury. In addition, maladaptive pain may sometimes result from the inappropriate recruitment of this powerful adaptation to severe bodily injury. Some clearly pathological conditions (e.g. sickle cell disease) and toxicities (e.g. from chemotherapy) may trigger the release of sufficient amounts and combinations of inflammatory and injury-related signals [110,111] to ‘incidentally’ recruit this complex adaptation for driving ongoing pain. If the recruited nociceptor plasticity mechanisms are a product of positive evolutionary selection, they are more likely to be robust and to involve substantial redundancy than are purely pathological mechanisms. Multiple mechanisms that are partly redundant have been found to contribute to ongoing nociceptor activity induced by injury and inflammation [37,112] (A. G. Bavencoffe, M. A. Odem, S. C. Berkey, J. J. Herrera, E. R. Lopez, C. W. Dessauer, E. T. Walters 2019, unpublished observations). Such redundancy reduces the chances that clinical targeting of just one of many contributing mechanisms can be sufficient to alleviate chronic pain. Conversely, physiological constraints may limit the number of mechanisms available to natural selection for overcoming especially difficult functional obstacles. One such challenge is how, after severe injury, a nociceptor can generate persistent ongoing activity with appropriate discharge patterns and frequencies despite extreme changes in surrounding tissue conditions over long periods of time. The identification of the major biological obstacles and solutions related to persistent generation of ongoing activity in nociceptors after severe bodily injury might lead to new and relatively specific targets for treating chronic pain.

Data accessibility

This article has no additional data.

Competing interests

I declare I have no competing interests.

Funding

During the article's preparation, the author's relevant research and scholarship were supported by NIH grant nos RO1NS091759 and RO1NS111521, and by funds from the Fondren Chair in Cellular Signaling and a Ray A. and Robert L. Kroc Faculty Fellowship.