Accepted

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'.

Enormous progress in understanding the mechanisms that mediate pain can be augmented by an evolutionary medicine perspective on how the capacity for pain gives selective advantages, the trade-offs that shaped the mechanisms, and evolutionary explanations for the system's vulnerability to excessive and chronic pain. Syndromes of deficient pain document tragically the utility of pain to motivate escape from and avoidance of situations causing tissue damage. Much apparently excessive pain is actually normal because the cost of more pain is often vastly less than the cost of too little pain (the smoke detector principle). Vulnerability to pathological pain may be explained in part because natural selection has shaped mechanisms that respond adaptively to repeated tissue damage by decreasing the pain threshold and increasing pain salience. The other half of an evolutionary approach describes the phylogeny of pain mechanisms; the apparent independence of different kinds of pain is of special interest. Painful mental states such as anxiety, guilt and low mood may have evolved from physical pain precursors. Preliminary evidence for this is found in anatomic and genetic data. Such insights from evolutionary medicine may help in understanding vulnerability to chronic pain. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Animals have quick-acting nociceptive reflexes that protect them from tissue damage. Some taxa have also evolved the capacity for pain. Pain appears to be linked to long-term changes in motivation brought about by the aversive nature of the experience. Pain presumably enhances long-term protection through behaviour modification based, in part, on memory. However, crustaceans have long been viewed as responding purely by reflex and thus not experiencing pain. This paper considers behavioural and physiological criteria that distinguish nociception from potential pain in this taxon. These include trade-offs with other motivational systems and prolonged motivational change. Complex, prolonged grooming or rubbing demonstrate the perception of the specific site of stimulus application. Recent evidence of fitness-enhancing, anxiety-like states is also consistent with the idea of pain. Physiological changes in response to noxious stimuli mediate some of the behavioural change. Rapid avoidance learning and prolonged memory indicate central processing rather than mere reflexes. Thus, available data go beyond the idea of just nociception. However, the impossibility of total proof of pain described in ways appropriate for our own species means that pain in crustaceans is still disputed. Pain in animals should be defined in ways that do not depend on human pain experience. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Cannabinoid-based therapies have long been used to treat pain, but there remain questions about their actual mechanisms and efficacy. From an evolutionary perspective, the cannabinoid system would appear to be highly conserved given that the most prevalent endogenous cannabinoid (endocannabinoid) transmitters, 2-arachidonyl glycerol and anandamide, have been found throughout the animal kingdom, at least in the species that have been analysed to date. This review will first examine recent findings regarding the potential conservation across invertebrates and chordates of the enzymes responsible for endocannabinoid synthesis and degradation and the receptors that these transmitters act on. Next, comparisons of how endocannabinoids modulate nociception will be examined for commonalities between vertebrates and invertebrates, with a focus on the medicinal leech . Evidence is presented that there are distinct, evolutionarily conserved anti-nociceptive and pro-nociceptive effects. The combined studies across various animal phyla demonstrate the utility of using comparative approaches to understand conserved mechanisms for modulating nociception. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.

Injury occurring in the neonatal period in mammals is known to induce plasticity in pain pathways that may lead to pain dysfunction in later life. Whether these effects are unique to the mammalian nervous system is not well understood. Here, we investigate whether similar effects of early-life injury are found in a large-brained comparative model, the cephalopod . We show that the peripheral nervous system of undergoes profound and permanent plasticity after injury of peripheral tissue in the early post-hatching period, but not after the same injury given in the later juvenile period. Additionally, both innate defensive behaviour and learning are impaired by injury in early life. We suggest that these similar patterns of nervous system and behavioural remodelling that occur in squid and in mammals indicate an adaptive value for long-lasting plasticity arising from early-life injury, and suggest that injuries inflicted in very early life may signal to the nervous system that the environment is highly dangerous. Thus, neonatal pain plasticity may be a conserved pattern whose purpose is to set the developing nervous system's baseline responsiveness to threat. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.