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«October 2009 SCIENTIFIC COORDINATOR Pierre Le Neindre, Senior research scientist, INRA (French National Institute for Agricultural Research) ...»

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The disabled A number of recent studies using validated measurements, show that people with intellectual disabilities exhibit specific reactions in response to pain arising from their condition, even if they have more difficulty locating it or if they respond to it more slowly due to modified sensory perceptions, impaired language or communicative Expertise scientifique collective "Douleurs animales" 25 expressions, or variability in basal levels. These specificities explain the difficulties of using conventional clinical examination. Interpretation is hampered by problems with verbal communication and pre-existing neurological disorders. It has been shown that cross evaluations by those close to the patient and unfamiliar observers provide a good indication of the patient’s state of pain and discomfort provided a validated tool is used.

Pain in children For children aged 0-5 years, the presence of pain that can be presumed to be enduring should be sought based on the differentiation between the various manners in which the child beckons. The diagnosis can only be made by gathering the accounts given by all those involved with the child (nurse, paediatric nurse, physiotherapist, psychologist, occupational therapist, nursing auxiliary, doctor...) and trying to identify patterns that express discontent, desire for affection, "physical pain" and psychological distress. The child should then be examined using identified means of communication, in peaceful and caring surroundings and in a serious, rigorous, calm and progressive manner.

Pain in the human foetus The case of foetal animals, mammalian foetuses in particular, does not fall specifically within the framework of the present study. However, the use of certain foetal tissues from animals prompted the examination of the sampling procedures used and the potential negative effects they could give rise to. In line with the approach adopted where data on human pain are presented so as to clarify the understanding of the mechanisms at work in animal species, here reference is only made to cases involving human foetuses where the question of pain was examined.

Available data have shown that in the human foetus, pain pathways as well as cortical and sub-cortical centres involved in the perception of pain are fully developed in the last third of pregnancy. The neurochemical systems currently known to be associated with the transmission and modulation of pain are functional. However there is no data to determine whether activating these structures involved in pain actually results in a newborn infant feeling pain in a similar manner to a child or an adult. While it has been demonstrated that the foetus develops a hormonal stress response to invasive procedures (an increase in stress hormones circulating in the bloodstream), it is not possible to conclude that the foetus feels pain.

2.2.3. The current definition of pain for humans The definition of pain has evolved over the last three decades. Pain experienced and described by patients despite the absence of an identifiable pathophysiological cause is now also listed in the classifications. The normalised protocols for the treatment of pain have been expanded in parallel, accompanied by the appearance of patient charters and awareness slogans (“stopping the pain is a patient’s right”). Instead of just trying to sedate pain the concern now is to anticipate the likely experience of pain in conjunction with therapeutic interventions The definition used here is the one which has been adopted worldwide by the IASP: “pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.

This definition refers to pain without stimulus of external origin, which shows the existence of pain of central origin, in other words being literally fabricated by the brain.

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2.3.1. The elements of pain Nociception The term nociception (from the Latin nocere, to harm) was introduced in the early 20th century to characterize the ability to specifically detect nociceptive stimuli which have in common the ability to threaten the integrity of tissues or of the body and to activate a set of sensory organs, the nociceptors. Nociception is considered as an alarm system that protects the body by triggering behavioural and reflex responses (somatic and vegetative responses) whose purpose is to suppress the cause and to limit the negative consequences. It contributes to the dynamic maintenance of general physiological equilibrium (homeostasis).

Nociceptors are made of thin unmyelinated nerve fibres which are undifferentiated at their end. They are found in varying densities depending on the innervated tissues. Some tissues, which are part of solid organs such as the brain or the liver, lack nociceptors. Nociceptors are preferentially sensitive to noxious stimuli and many of them, named polymodal nociceptors, respond indiscriminately to several types of stimuli whether they are mechanical, thermal, or chemical (Figure 2). Nociceptors send information directly to the spinal cord (for the body) or to cranial nerve nuclei (for the head) via bundles of sensory nerves. At the level of the medulla network, the organization of the afferents makes it possible to localize the source of information on the basis of a spatially ordered neural architecture. This organization constitutes the basis of body representation and the substrate for spatial location of noxious stimuli borne by the body or coming from the viscera (analytical component of sensation).

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Figure 2. The peripheral sensitive afferents of nociception in humans (J.

Servière, personal communication) Nociceptors are located in peripheral tissues (joint, muscle, skin, viscera) and their nerve fibres conduct the information to the spinal cord via sensory nerves (through the dorsal horn of the grey matter). The cell bodies of the sensory neurons are located on both sides of the spinal cord in the dorsal root ganglia. The synaptic junction is anatomically located in different cell layers of the dorsal horns depending on the tissue of origin. Superficial layers (I & II) receive signals from the skin whereas signals from visceral organs reach a deeper layer of cells (V).

Expertise scientifique collective "Douleurs animales" 27 From peripheral mechanisms to brain integration Pain is more than just a discriminative sensory experience enabling the determination of the characteristics (intensity, duration and location on the body) of a noxious stimulus. It is associated with an emotion that is caused by the confrontation with a situation involving the interpretation of reality. The aversive emotional state associated with the sensation of pain is a powerful motivation to perform an act of protection. This emotion whether "unpleasant" (illustrating the sensory component) or "aversive" (illustrating the behavioural component) is an intrinsic part of painful experience. Emotion is indissociable from pain experience which makes pain a more complex sensation than touch, vision, or hearing. Because of its profound aversive nature, pain has strong abilities to capture the subject's attention, to interfere with any other activities and to mobilize resources and defence strategies.

Pain can be classed in three categories according to pathophysiological mechanisms: acute or physiological pain, inflammatory pain, and neuropathic pain. Various function modes of the somatosensory system (the sensitivity of the body) are at the origin of these three categories. Pain of different kinds may co-exist, leading to "mixed" pain that is often difficult to diagnose and treat. Acute pain is often associated with inflammatory pain as, for example, after tissue damage or after surgery. This is called "pain due to excessive nociception”.

During an inflammatory episode, nociceptor responses are modified leading to increased sensitivity, or even to the involvement of receptors that were initially "silent" when the tissue was intact. The pain threshold is consequently lowered so that even a gentle touch can become painful (allodynia) while a noxious stimulus is perceived more intensely (hyperalgesia). Hyperalgesia may result from a disturbance in receptor peripheral sensitivity as well as from a modification in pain thresholds of central origin due to the control of descending pathways from the brainstem and spinal cord interactions. In this case, pain may extend beyond the duration of stimulation or may even occur spontaneously, after a reorganization of the neural networks involved. Such changes promote healing by adjusting reactions and behaviours such as resting the injured area and protecting it through an analgesic posture.

Neuropathic pain may result from long-term consequences of an injury (e.g. due to amputation) or from a functional change of the somatosensory system which then evolve in an abnormal and inappropriate way. Persistent pain with no biological purpose has a pathological nature. It develops independently of whether the initial injury is maintained or not, and relies on mechanisms of neural plasticity. In the case of neuropathic pain, the physiological system that is normally involved in nociception generates the sensation of pain itself.

It is possible to follow the progression of events occurring in the nervous system from the peripheral activation of nociceptive responses to the integrative responses in the brain structures responsible for the onset of the painful sensation. Cortical and diencephalic nuclei which are responsible for processing emotions, memory, basic consciousness (awareness, alertness…) are activated in parallel with motor pathways which organize movements and protective behaviours.

Once in the spinal cord, nociceptive signals are simultaneously directed towards both spinal motor neurons responsible for reflex activities, and to higher brain centres. Nociceptive and thermal sensory information follow a specific ascending pathway in the spinal cord (bundles of nerve fibres assembled into distinct anatomical pathways or ventro-lateral tract). Functional brain-imaging techniques (functional magnetic resonance imaging and positron emission tomography) have shown in humans that the cingulate and insular cortices are particularly activated.

These structures, belonging to the limbic system, are crucial in generating emotions. To a lesser extent, the somatosensory, primary and secondary cortices are also activated by noxious stimuli. It appears that it is a whole network of brain areas that is responsible for the perception of pain and not just a unique structure (Figure 3).

28 Expertise scientifique collective "Douleurs animales" Figure 3. The spinothalamic tract. This is the main pathway for transmission of signals from nociceptors and thermoceptors (in primates) (Jacques Servière personal communication) After the initial relay in the spinal cord, nerve signals are conveyed in parallel to higher centres via two types of pathways that transmit different components of pain. The signal is relayed differentially according to two major functional characteristics. The alarm and discriminative sensory components of the stimulation (location in the body, intensity, duration, repetition...) are conducted through the spinal cord by nerve fibers of the "lateral pathway" which project into the ventral posterior lateral nucleus of the thalamus and then reach the S1 & 2 somatosensory cortex. The "unpleasant" component of the sensation is transmitted via the slow "medial pathway" from which the fibres are distributed to a set of nerve centres located along the antero-posterior axis of the brain.

The pain response system allows the analysis of nociceptive information and triggers protective reactions. It differs from other sensory systems (vision, hearing) in that it necessarily activates structures involved in processing events that are beyond the mere sensory analysis. Pain networks are at the junction of the domains of physiology and psychology because they can trigger simple vegetative responses (heart rate, levels of adrenaline...), protective motor responses (flight reflexes), or more complex behavioural strategies (specific postures, withdrawal strategies, social isolation) that may be associated with complex emotional experiences.

Emotions From the cognitivist viewpoint, emotions are defined as complex affective reactions combining body and brain functions. These reactions include a subjective mental state (anger, fear, anxiety, depression, compassion, love...), a drive to flee or attack which may or may not be expressed behaviourally, and physiological changes (increased heart rate, blood pressure, altered muscle tone...). Some of these changes prepare the individual for actions of Expertise scientifique collective "Douleurs animales" 29 sustainable duration. Additional observable responses (posture, gestures, facial expressions...) may serve as signals to communicate what it is experiencing, or manipulate, to the signaller’s benefit, how others interpret its motivational/emotional state.

Negative human emotions are the consequences of dramatic events in a person’s life, associated with their lot, the values and ideas they hold close to their heart as well as their beliefs about themselves and the world they live in.

The emotion is triggered by a personal assessment of the meaning of what is happening. The dramatic episode varies from one emotion to another, each emotion having its own history. The onset of emotions involves complex processes to assess the current situations. These processes are correlated with the activation of brain structures that are relatively recent on a phylogenetic scale.

The functional interactions between phylogenetically recent structures (like the cerebral cortex which is particularly developed in nonhuman primates and in humans) and phylogenetically older structures which are also found in non-mammalian species (limbic system, hypothalamus, brainstem nuclei such as the periaqueductal grey), show how different anatomical levels of the nervous system interact. These complex interactions modulate the autonomic responses associated with pain, or may modulate the experience of pain itself (cf. response thresholds of the receptor). Thus, in some rodents, the response thresholds to noxious thermal stimuli are modulated by social emotional components (presence of a conspecific, hierarchical position).

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