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Neurol Sci (2011) 32 (Suppl 1):S61S66 DOI 10.

1007/s10072-011-0539-y

INVITED LECTURE

Pain as an evolutionary necessity


V. Bonavita R. De Simone

Springer-Verlag 2011

Abstract The proposed title Pain as an evolutionary necessity could lead to a broad debate with implications covering many chapters of the medicine and particularly of clinical neurology. In the present perspective, the discussion will focus on migraine and cluster headache chosen as elective examples of biological and not only clinical conditions, that unveil the bond between pain and necessity. Migraine, cluster headache, and perhaps other primary headaches begin to be depicted in terms of recurrent activation of innate bio-behavioral specic patterns, with a crucial and highly conserved evolutionarily adaptive signicance. The pan-mammalian sickness behavior and the ght or ight response, selectively activated by different kinds of pain, are here proposed as paradigmatic of migraine and cluster headache attacks associated behaviors, allowing to reformulate these forms as the inappropriate recurrent presentation of coordinated allostatic processes, modeled along million of years of natural evolution. In this light, all the multifaceted characteristics of migraine and cluster headache attacks can be reinterpreted as complex and integrated allostatic defensive reactions to an inescapable or to an escapable pain, respectively aimed to the restoration of biologic homeostasis through a temporary disengagement from active interaction with environment (migraine associated sickness behavior) or, on the contrary, to promote the coordinated biological changes
V. Bonavita Istituto di Diagnosi e Cura Hermitage Capodimonte, Naples, Italy R. De Simone (&) Department of Neurological Sciences, Headache Centre, University Federico II of Naples, Via Pansini, 5, 80131 Naples, Italy e-mail: rodesimo@unina.it

preparatory to emergency and defensive behaviors (cluster headache-related ght or ight response). Keywords Pain Evolution Migraine Cluster headache Sickness behavior Fight or ight response

Introduction Pain as an evolutionary necessity is a title that may rise an immediate rejection, if it is not clear that the term is here referred to the acute pain that signals a risk: the risk that the disease, which pain is part of, could reversibly damage or even destroy without any possibility of appeal the physical or mental integrity of one of us. Unfortunately, as Aeschylus warned nobody, except the gods, can live time forever without any pain. For human beings, the experience of pain, mute or screamed, is inevitable, and has led to two opposite strategies: 1. taking distance from the pain, for which we become impassive, we deny the recognition of pain or its power over us, for which we dominate the fear. It is the distance of the Stoics, of martyrs of a faith, of the torture victims who were able to resist; to let ourselves to be involved with pain, because suffering puries and God will give us merit.

2.

Two great traditions of our culture express this second strategy in pain cognition: the rst of biblical origin that is met in Ecclesiastes argues that if knowledge increases, so does the pain: qui auget scientiam auget et dolorem. There is the common idea in this statement that is better not to know, it is better to resign to fate. The other strategy could be represented by the reversed form of the Ecclesiastes sentence qui auget dolorem auget

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scientiam, but doing so we are in Greek tragedy or in Christian tradition; they both are not willing to accomplish the knowledge of pain, instead lean toward to the knowledge that is reached through the pain. Thus we slip from the pain to the suffering, for which Lev Tolstoj wrote: if there were no suffering, man would not know his limitations, would not know himself, but with Tolstoys words about the suffering, we come back to Aeschylus and pain from which only gods are immune. Indeed, the pain cannot live without the suffering, because it is both a perceptive and emotional experience: a homeostatic emotion as argued by A. D. Craig: the human feeling of pain is both a distinct sensation and a motivation that is a specic emotion that reects homeostatic behavioral drive, similar to temperature, itch, hunger and thirst [1]. If so, it will be different in the morpho-functional substratum of necessary pain, to which this reading is addressed, and of unnecessary pain about which Arthur Schopenhauer warned on two fundamental patient rights: do not suffer and to maintain dignity and an acceptable quality of life during the disease.

from or counteract the noxious stimulus and the threat posed by the environment to body homeostasis [1]. This new conception of pain makes it closer to other sensory modalities in which a stimulus, more or less complex, is perceived at the same time in terms of emotion, motivation and behavior, such as itch, temperature, sexual desire, hunger and thirst [1]. Pain is thus necessary to organism survival, provided it is considered as the starting station of a process that involves multiple structures at different levels of CNS, linked together in a functional network and responsible for complex and coordinated responses, aimed to maintain or restore internal homeostasis of the body.

Visceral pain and somatic pain: distinct neural networks for distinct adaptive goals The conceptualization of pain as a powerful homeostatic emotion enables its interpretation in terms of bio-behavioral response according to different stimuli and especially to the context in which pain is generated. In this key, the rst crucial distinction should be made between escapable pain, i.e. the pain perceived as the indicator of a threat from which we can and must try to escape from, or that need to be neutralized, and inescapable pain, i.e. the pain that indicates a problem that cannot be successfully faced up, or that would be even counterproductive trying to control by any active defensive behavior. Escapable and inescapable pain implies different sensitive modalities and pathways. A-delta- and C-ber nociceptors transmit different qualities of pain: pricking, well localized the rst and burning, diffuse the second [7]. Characteristically, escapable pain results from the activation of A-delta nociceptors, highly represented in the skin, and transmit the pain perceived mainly at cutaneous level, whereas inescapable pain mostly comes from the activation of C bers specially localized in the deep viscera, meninges and cerebral vascular tree included, and is implied in the activation and transmission of visceral homeostatic pain [8]. Escapable and inescapable pain also maintain distinct pathways to the brain, especially in the periaqueductal gray region (PAG). In the rat, most of C-ber activated neurons (inescapable pain) project to the ventrolateral PAG whereas A-delta nociceptors (escapable pain) mainly activate the dorsolateral/lateral PAG [7]. A similar distinction is maintained for even more rostral projections in the hypothalamus, amygdala, and forebrain [9, 10]. It is noteworthy that, at least for visceral homeostatic pain, the neural network involved in its processing almost completely overlap with the so-called pain matrix [11], the network of brain areas activated by pain arising from

Background The inherited condition known as congenital insensitivity to pain is a frequent cause of premature death due to complications of trauma and injuries [2]. This is probably the most striking evidence of the defensive role carried by our ability in perceiving pain. The evolving concept of pain has led to the reformulation of its meaning by placing it in a much broader frame [3, 4]. Currently, we look at pain not only in terms of a polymodal sensory function activated by specic triggers and characterized by dened set of qualities and a high capacity of topographic discrimination, but also as a fundamental component of body homeostatic control system that ensures maintaining the proper biological balance underlying the organs and systems functioning, and which is constantly perturbed by the continuous interactions between the organism and the very variable conditions of the environment [5]. According to this view, rather than merely a value of somatic sensation, pain is one of the main mechanisms promoting the complex and coordinated sensorial-emotivebehavioral experience underlying the allostatic processes, a wide term that encloses all mechanisms nalized in restoring homeostasis, including anticipatory behavioral measures to prevent whatever impending derangement of the homeostatic balance [6]. Allostatic processes include the generation of emotions at different affective tones, the modulation of powerful motivational instances, and nally, the implementation of appropriate behaviors to escape

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different sources and considered implied in the development of some other primary pain disorders such as bromyalgia, neuropathic pain and allodynia [12, 13] and currently viewed as a new therapeutic target for some primary headaches, chronic migraine and cluster headache included [14, 15]. If this is so, changes observed in the brain areas involved in pain processing might reect the consequence rather than the cause of primary painful syndromes, despite the efcacy shown by their selective stimulation with electric devices. Interestingly, these two types of pain promote two different patterns of behavior. Inescapable pain leads to passive coping strategies characterized by a disengagement from the external environment and includes motor quiescence, hyporeactivity, decreased vigilance, reduced responsiveness to tactile or visual stimuli, sympathoinhibition and vasodepression. This complex defensive reaction has been termed by Hart as sickness behavior [16] to emphasize that the behavior of a sick individual is not a maladaptive and undesirable effect of illness, but rather a highly organized behavioral strategy that is at times critical to the survival of an individual. On the other hand, escapable pain leads to the so-called ght or ight defense reaction (active emotional coping) with the subject trying to avoid or running away from the nociceptive stimulus and includes a general sympathoexcitation resulting in hypertension, tachycardia and redistribution of regional blood ow [8]. These changes are preparatory to emergency and defensive behaviors and support the engagement with the environmental threat or the escape from it. Thus, the sickness behavior and the ght or ight response can be considered among the behavioral correlates of visceral and somatic pain, respectively. They are innate behaviors shared by all mammalians [17, 18], with a crucial adaptive signicance, and therefore, evolutionistically selected over millions of years.

Migraine and cluster headache attacks as sickness behavior and ght or ight response paradigm If the nalistic interpretation of pain allows conceptualizing the sickness behavior and the ght or ight response as the opposite poles of the evolutionary modeled behavioral correlates of pain, then every pain can be conjecturally allocated within an ideal line joining such two extremes. The last, illuminating review published by Pasquale Montagna and his co-workers, is a very suggestive re-conceptualization of the complex migraine and cluster headache attacks clinical presentation within the wider frame of the innate behavioral correlates of different kinds of pain [19]. In this light, the inextricable puzzle represented by the multifaceted clinical characteristics of the migraine pain

attack can be solved considering its striking similarity with the innate behavioral adaptive response represented by the sickness behavior. Actually, migraine can be considered as a stereotyped cascade of coordinated neural processes leading to a complex clinical picture in which the head pain is only the most clearly perceived component, and may even lack in some cases (as in aura without migraine or in migraine precursors of the infancy). According to Blau [20], the development of pain in migraine attacks is preceded (up to 2 days before) by a prodromal phase that includes fatigue, general malaise, neck stiffness, difculties in mental concentration, mood changes, pallor, blurred vision and modications in eating and drinking habits with hyperphagia or, on the contrary, food avoidance. A typical migraine aura may follow the prodromal phase in a minority of patients. A moderate to severely disabling pain opens the headache phase, and is associated with nausea and possibly vomiting and with phono- and photophobia, gastric paresis and osmophobia. It is noteworthy that pain is consistently aggravated by even light routine activity such as walking or climbing stairs. The resolutory phase that may last up to 2 days after the resolution of pain, is characterized by tiredness, weakness, fatigue, a minor and residual head pain, difculties in concentrating, somnolence, yawning and mood changes either in depressive or hypomaniacal direction. The entire clinical picture may ultimately terminate with sleep [21, 22]. The behavior of migraine patients during the attack is characteristic, with patients seeking to reduce movements or to lay down immobile, as far as possible from any environmental stimuli, particularly light, odors and noise. Most of them actively seek to fall asleep, thus interrupting any possible interaction with environment. All the above symptoms and signs, together with their behavioral correlates, are doomed to remain totally elusive unless re-conducted into the frame of the innate defensive reaction represented by the sickness behavior. In this light, all the multifaceted migraine attack characteristics can be fully explained as a complex and integrated allostatic defensive reaction to an inescapable pain that allows the restoration of biologic homeostasis through a temporary disengagement from active interaction with environment. The neurochemical basis of such reaction might involve the cytokines system, implied in hyperalgesia and allodynia as well as in visceral homeostasis signalling [23] and in the so-called immune-to-brain communication [19]. The excruciating pain of cluster headache (CH) attacks is associated to a quite different behavior. CH patients cannot sit still during an attack [24] and such restlessness is considered as a major diagnostic criterion [25]. Actually, pain in CH is associated with extreme restlessness, with patients frantically walking around, sitting, rocking or kneeling, clutching the affected side of the head [26]. If the

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patient is awakened by the onset of an attack in the early morning hours, he usually cannot remain in bed but is forced to continuously pace the oor at least during the peak of the attack. Such behavior does not help in reducing pain intensity, and is perceived as inappropriate by the patient, that may express doubts about his sanity. As a fact, suicide and self-hurting behaviors have been reported, and aggressive behavior during the attack may result in legal consequences [27]. The stereotyped behavior that characterize CH patients is therefore opposite to the avoidance pattern typical of migraineurs and closely resembles the behavior of an individual ghting against an escapable pain or running away from it, thus a ght or ight response. Pain in CH is possibly related to the activation of nociceptive A delta-ber cutaneous afferents in the trigeminal pathway. Such afferents in turn activate distinct trigeminal and brainstem pathways, and distinct rostral areas at the level of the mesencephalic PAG columns and posterior hypothalamus. These brain areas are involved in active coping behavior, including the facilitation of aggressivity and rage reactions [19]. The ght or ight response implies the emission of aggressive and combative behaviors and/or the eeing from potentially threatening situations, such as being attacked by a predator. The reaction is associated with increased production of catecholaminergic amines and sympathoexcitation leading to a coordinated rise in arterial pressure, heart and breathing rates and with a modulation of segmental blood ow preparatory to the active engagement with the environmental threat. As proposed by Pasquale Montagna and co-workers, the behavioral signicance of pain in the primary headaches is therefore different, escapable in CH (the prototypic trigeminal autonomic cephalgia), while inescapable in the migraine headaches. This difference accounts for the opposite behaviors observed in these two paradigmatic conditions. In the light of this original pathogenetic perspective, we can regard to primary headaches as a reection of evolutionary modeled adaptive behavioral responses, and is therefore possible re-conceptualize these disorders as integrated response to homeostatic imbalance or derangement. Such new perspective has many important consequences on the way primary headaches stereotyped phenotypes are to be intended and requires the redenition of the primary headache attack not as a disease itself, but as a more or less inappropriate recurrent triggering of specic adaptive and innate allostatic behaviors.

of primary pain in headaches eld. If the recurrency of attacks, rather the attack itself, may still be regarded as a disease [6, 28], the primary event is no longer the cascade of biochemical changes leading to headache attacks, but the mechanisms implied in the triggering of these complex innate adaptive responses. Following this road, we immediately face with a dicotomy: (1) migrainous brain is hyperexcitable (probably as a consequence of a genetically and/or environmental driven increased susceptibility to energetic failures) [29, 30]. If this is so, the primary event should to be traced back to the mechanisms underlying such neural energetic imbalances. This means that headache attacks could be regarded as a fully appropriate response aimed to the restoration of an intrinsically impaired homeostasis; (2) the failure might consist in the genetically and/or environmental driven lowering of the attacks triggering threshold, resulting in the inappropriate periodic recurrences of acute attacks.

Evolutionary advantages of migraine If the rarity and the periodicity of cluster headache makes its evolutionary signicance a eld in which it is more difcult to venturing hypothesis, only highly speculative, it is possible for migraine to formulate hypotheses to explain its high and probably slowly increasing prevalence [31, 32]. The pivotal Montagna and co-authors work leads back the protean migraine to a complex and articulated, but very consistent, bio-behavioral innate defensive reaction, disclosing, at the same time, the secret of the conceptual elusiveness of this condition that lasts since immemorial time. Assuming that migraine is the result of equally shared genetic and environmental promoting factors [33], the questions that remain unanswered is why it is still so prevalent in general population. In a very interesting paper, Elizabeth Loder [34] provided a number of hypothesis that can suggest the possible evolutionary advantages carried by migraine. Whether the recurrence of migraine attacks represents the expected phenotype of an intrinsically oxidative derangement of the brain, rather than a periodic, inappropriate activation of an innate physiological pattern (of an evolutionistically modeled defensive behavior), Loder wonders about what has prevented migraine disappearance by natural selection, reasoning about the possible evolutionary benecial consequences of the increased susceptibility to migraine, powerful enough to overtake the negative effects that the recurrent disability of migraine attack actually determines. Following the general frame of the recently born branch of medical investigation called Darwinian medicine [35], Loder has discussed some possible scenarios that can explain the persistence of migraine despite its disabling consequences:

Where the genetic research for primary headaches is to be focused? The proposed change in the pathogenetic perspective of primary headaches also requires the revision of the concept

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Migraine as a defense mechanism. In this view, the behavioral meaning of migraneous inescapable pain fully overlaps with the sickness behaviour. Moreover, the low threshold and the reduced habituation to repeated sensory stimuli such as light, noise and odors as well as the susceptibility to physical and/or mental stress, to lack of sleep or to fasting (all powerful migraine triggers) may suggest an enhanced skill of migrainous individuals in avoiding toxin ingestion or inhalation, and to promptly detect and avoid environmental threats. These traits could have been favored by the forces of natural selection for their high adaptive value despite the periodic disability induced by headache recurrence. In this perspective, migraine may be described as a trade-off between the disadvantages and advantages of evolution, a hypothesis proposed separately in Loders work. Migraine as a result of conicts with other organisms. The susceptibility to respond with a headache-dependent intracranial vasodilatation early in the development of an inammatory CNS reaction to infective threats may result in a stronger immune response against pathogens, therefore enhancing individual survival and fertility. Migraine as a result of novel environmental factors. Migraine may be the result of the sudden change of natural environment and human beings lifestyle, after millions of years of a relatively steadiness of these factors. In this light migraine could represent a trait that emerges from such changes and that natural selection has not yet had a chance to eliminate. Headache as a design contrast. Older brainstem and diencephalic structures essential to organism survival may have revealed not perfectly compatible with the more recent cortical development. This could account for the univocal pertinence of migraine to human beings and suggests that the recent evolutionary changes in the brain are responsible of the peculiar susceptibility to migraine of our species.

The extraordinary prevalence of migraine, associated with its possibly ongoing epidemiological expansion, allows to postulate the existence of evolutionary advantages of migraine. In this light, primary headaches could be re-conceptualized as a necessary, although evolutionistically affordable, biological cost.
Conict of interest The authors declare that there is no actual or potential conict of interest in relation to this article.

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