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In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes essentially concerned the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been checked with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area whose amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only - and not in other brain areas - was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief were taken in account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the peri-acqueductal grey (PAG) and, at least in some instances, with the involvement of endogenous opioids., (© Société de Biologie, 2014.)

Pain is a physiological sensation which aim is to alert for an upcoming danger that may threaten the individual. This system includes peripheral nociceptors that initiate the nociceptive message. Then, the information is conveyed to the brain through the spinothalamic tract that projects to the thalamus, insula, SII and other areas. In clinical situations, a dysfunction of this nociceptive system explains chronic pain that can be simply classified into 3 subtypes according to pathophysiological mechanisms. Case 1: the nociceptive system is functioning normally, and provides (appropriately) a pain message that informs the brain of a local inflammation, or cancer, or infection... This is the situation of chronic pain because of an excess of nociception. Case 2: there is a (past or present) lesion of the nervous system that induces a dysfunction in the pain system. This is the neuropathic pain. Case 3: between the two former cases, there is no evidence for a lesion in the nociceptive system, and there are no evidences for lesion at the peripheral level, but there are evidences of dysregulation(s). These are the cases of dysfunctional pain.

In this review, we summarize the contribution of functional imaging to the question of nociception in humans. In the beginning of the 90's, brain areas supposed to be involved in physiological pain processes were almost exclusively the primary somatosensory area (SI), thalamus, and anterior cingulate cortex. In spite of these a priori hypotheses, the first imaging studies revealed that the main brain areas and those providing the most consistent activations in pain conditions were the insular and the SII cortices, bilaterally. This has been confirmed with other techniques such as intracerebral recordings of evoked potentials after nociceptive stimulations with laser showing a consistent response in the operculo-insular area which amplitude correlates with pain intensity. In spite of electrode implantations in other areas of the brain, only rare and inconsistent responses have been found outside the operculo-insular cortices. With electrical stimulation delivered directly in the brain, it has also been shown that stimulation in this area only--and not in other brain areas--was able to elicit a painful sensation. Thus, over the last 15 years, the operculo-insular cortex has been re-discovered as a main area of pain integration, mainly in its sensory and intensity aspects. In neuropathic pain also, these areas have been demonstrated as being abnormally recruited, bilaterally, in response to innocuous stimuli. These results suggest that plastic changes may occur in brain areas that were pre-defined for generating pain sensations. Conversely, when the brain activations concomitant to pain relief is taken into account, a large number of studies pointed out medial prefrontal and rostral cingulate areas as being associated with pain controls. Interestingly, these activations may correlate with the magnitude of pain relief, with the activation of the PAG, and, at least in some instances, with the involvement of endogenous opioids.

Central post-stroke pain (CPSP) is known since the famous Dejerine-Roussy syndrome and its description has not improved. The subject has however been revived over the last decade thanks to advances in central nervous system imaging with magnetic resonance imaging (MRI), the description of allodynia functional phenomena with fMRI, the study of opioid receptors, and above all, the analysis of pain pathways by laser-evoked potentials. Progress has also occurred in CPSP treatment with motor cortex stimulation, which probably opens a period of neuromodulation of the cortical areas controlling pain. The thalamus plays a prominent role in this disorder of central control of pain.

The study of pain integration, in vivo, within the human brain has been largely improved by the functional neuro-imaging techniques available for about 10 years. Positron Emission Tomography (PET), complemented by laser evoked potentials (LEP) and functional Magnetic Resonance Imaging (fMRI) can nowadays generate maps of physiological or neuropathic pain-related brain activity. LEP and fMRI complement PET by their better temporal resolution and the possibility of individual subject analyze. Recent advances in our knowledge of pain mechanisms concern physiological acute pain, neuropathic pain and investigation of analgesic mechanisms. The sixteen studies using PET have demonstrated pain-related activations in thalamus, insula/SII, anterior cingulate and posterior parietal cortices Activity in right pre-frontal and posterior parietal cortices, anterior cingulate and thalami can be modulated by attention (hypnosis, chronic pain, diversion, selective attention to pain) and probably subserve attentional processes rather than pain analysis. Responses in insula/SII cortex presumably subserve discriminative aspects of pain perception while SI cortex is particularly involved in particular aspects of pain discrimination (movement, contact.) In patients, neuropathic pain, angina and atypical facial pain result in PET abnormalities whose significance remain obscure but which are localized in thalamus and anterior cingulate cortices suggesting their distribution is not random while discriminative responses remain detectable in insula/SII. Drug or stimulation induced analgesia are associated with normalization of basal thalamic abnormalities associated with many chronic pains. The need to investigate the significance of these responses, their neuro-chemical correlates (PET), their time course, the individual strategies by which they have been generated by correlating PET data with LEP and fMRI results, are the challenges that remain to be addressed in the next few years by physicians and researchers. To advance our knowledge of the mechanisms generating both abnormal pain and analgesia (drugs and surgical techniques) in patients is the main motivation of such anexciting challenge.

It would be simplistic to consider the reality of pain as nothing more than heightened sensitivity to the pain. There are actually five types of pain, and it is often difficult to distinguish between them. Whereas hypernociceptive pain is mainly treated with analgesics belonging to one of the three categories as defined by the WHO, the mechanisms and treatment of the other four types of pain are very different It is obvious that close co-operation between the various healthcare professionals is indispensable in the treatment of these patients, while keeping in mind that the physician is "a symbol, an intermediary, a medicine that's better than medicine: the medicine works because it's a symbol - it's a symbol because it works". (P. Queneau and G. Ostermann.)

Forty-nine subjects have been included in a randomized cross-over study evaluating acute hypocalcemia induced by calcitonin in the staging of multiple myeloma, and comparing 0.5 mg of human calcitonin and 100 IU of salmon calcitonin. Subjects were divided in 11 controls, 15 myelomas before primary treatment, 11 myelomas in plateau-phase and 12 in relapse. All the subjects had both tests with the two calcitonins at an interval of 3 days. Decrease of calcemia was important and similar in patients before primary treatment and in relapse (0.16 mmol/l mean value). Decrease was moderate in patients in plateau-phase (0.07 mmol/l mean value), similar to the decrease observed in controls. Decrease of calcemia was correlated with tumoral cellular mass in initial phase patients, but not in patients in plateau-phase. Both human and salmon calcitonins had similar effects on onset, magnitude and duration of hypocalcemia inside each group. This study confirms the interest of acute hypocalcemia test induced by calcitonin in the clinical staging of myeloma, and the similar effectiveness of both calcitonins in man.

Unlabelled: The aim of the study was to compare plasmatic levels of calcitonin obtained after intradermic (ID) and usual subcutaneous (SC) route of administration., Method: 6 volunteers between 18 and 40 years old received calcitonin 0.5 mg (Cibacalcin, Ciba-Geigy Laboratory) by ID and SC routes in a random order but at the same site of injection. Each administration was spaced by 8 days. Plasmatic levels were measured by R.I.A. before administration then 2 (M2), 7 (M7), 15 (M15), 30 (M30) minutes and 1 (H1), 2 (H2), 4 (H4), 8 (H8), 12 (H12) hours after each administration., Results: Tmax were at 23.6 +/- 10 min and 16.2 +/- 7.5 min for SC and ID routes respectively. With ID route, Tmax was reached simultaneously or earlier (3 times). Cmax is significantly higher with ID route. Neither mean plasmatic levels at each plasmatic dosage nor mean areas under the curve between 0 to 1,440 min or between 0 to 480 min (this latest AUC calculate to minimize the importance of calcitonin basal level) were significantly different with ID and SC routes. 16 mild side effects (8 with each administration) were observed in 4 subjects. They appeared before 5 min. and were transient (1 hour) for cutaneous manifestations, and later between hours 3 and 7 for nausea and vomiting or asthenia. The mean lowering of calcemia was 0.29 +/- 0.21 and 0.18 +/- 0.11 mmol/l respectively for SC and ID route. In this study ID and SC routes for calcitonin administration are not different with regard to plasma levels and side effects.

We report the fifth case of carcinoid tumour of Vater ampulla with Von Recklinghausen's neurofibromatosis. We have reviewed the literature and discussed the significance of such an association which seems fortuitous.