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Neuroscience Letters 581 (2014) 135–136

Contents lists available at ScienceDirect

Neuroscience Letters

jo ur nal ho me page: www.elsev ier .com/ locate /neule t

lenary Article

ortical Modulation of Pain: Comments on “Exacerbation of tonic butot phasic pain by entorhinal cortex lesions”

ackeline Moraes Malheirosa, Ruth Guinsburgb, Luciene Covolana,∗

Departmento of Phyisiology, Universidade Federal de São Paulo – UNIFESP, São Paulo 04023-062, BrazilDepartment of Pediatrics, Universidade Federal de São Paulo – UNIFESP, São Paulo 04023-062, Brazil

ven though it is clear that the perception of pain requires the activ-ty of higher cortical centers of the brain, the precise anatomicalssociation of these areas has remained largely unknown. Imag-ng studies in both humans and animals, mainly based on positronmission tomography (PET) and functional magnetic resonancefMRI) [4–6,13,14,20,22,25], have focused on the thalamus, primarySI) and secondary (SII) somatosensory cortex, the anterior cingu-ate area, the insula, the prefrontal cortex, the lentiform nucleusnd the cerebellum as major players in the higher processing ofain.

For most of the areas described above, the roles and patternsf connectivity are well-known. In short, the thalamus is the relaytation that conveys sensory, motor and autonomic informationrom the spinal cord and brainstem to specific cortical and sub-ortical regions and vice versa. Spinothalamic pathways terminaten specific thalamus nuclei as the ventroposterolateral and ven-roposteromedial which in turn project to SI and SII. Primaryomatosensory cortex is implicated in localize pain [3], but whenonsidering the abundance of the dorsal horn projection of myelin-ted afferents to it, the SI seems to support abilities of normalubjects to localize skin stimuli and discriminate between sensoryttributes that include pain intensity (for review, see Ref. [26]). TheII cortex seems to have an important role in recognition, learningnd memory of painful events [21]. Similar to the somatosensoryortex, other regions as the anterior cingulated area, the insuland the prefrontal cortex, which receive direct or indirect projec-ions from limbic structures, are consistently activated by noxioustimulation. It was recently demonstrated by fMRI that prefrontal,arietal and anterior cingulate cortex are involved in expectancy-

nduced modulation of pain [14].In addition the above mentioned neocortical areas, the

rchicortex (hippocampus) has long been related to higher pro-

essing/perception of pain [10]. However the exact mechanismsnderlying such effects have been slowly uncovered. Recent studiesave demonstrated that the natural ability of hippocampal dentate

∗ Corresponding author at: Rua Botucatu, 862 5◦ andar, Brazil.el.: +55 1155764848x2006.

E-mail address: lcovolan@unifesp.br (L. Covolan).

ttp://dx.doi.org/10.1016/j.neulet.2014.08.013304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.

granule cells to proliferate in adulthood could be affected by neona-tal noxious stimulation. In response to inflammatory nociceptionon postnatal day 1 (P1), the granule cell layer of the hippocam-pus shows an increase in mitotic rate during adolescence [15–17],which has raised questions about the role played by hippocampusin the long term nociceptive processing. Dentate granule cells ofthe hippocampus have been related to the formation of associativememories [1], which are essential to define the semantic proper-ties of stimuli, since the meaning of a stimulus may be associatedwith other stimuli [2]. It has been demonstrated that chronic painis associated with the reduction in right hippocampus volume inaged women [8] and that pain interferes in processes of memoryencoding, which is associated with reduced activity in the samearea, It has been suggested that pain is related to disruption ofencoding and, thus, interferes with an early stage of memory for-mation [9]. Accordingly, ten year-old former preterm infants whoexperienced stressful routine interventions in intensive care unitsrate medical-related pain pictures as more intense that other painpictures, indicating that they may have more pain memories thanage-matched full term infants [12].

Considering that, entorhinal cortex (EC) is the major extrahip-pocampal source of inputs to the dentate hippocampus [27,28], therecent study of Yu Zhang et al. addresses the question of whetherthe EC is involved in pain processing [30] in adult rats. In this ele-gant study, the authors investigated how MEC (medial entorhinalcortex) and LEC (lateral entorhinal cortex) lesions could alter phasicand tonic pain responses induced by hot plate and intra-plantar for-malin injection, respectively. The results obtained have importantimplications. In the hot plate test, neither MEC- nor LEC-lesionedrats were different from sham rats. Similarly, there were no dif-ferences in the first phase of formalin test. In addition, the majorfinding of the study is that MEC and LEC lesions increased paw lick-ing in the second phase (tonic phase) of formalin test. These findingsdemonstrate a specific role played by the EC in the processing oftonic pain. It is interesting to note that, as the authors noted, sev-eral reports have ascribed a pro-nociceptive role to hippocampus

[7,11,18,19,23,24,29], so it could be expected that bilateral MEC orLEC lesion would cause an anti-nociceptive effect. But the appar-ent discrepancy between Zhang et al. [30] findings and previousones [7,11,18,19,23,24,29] highlights the importance of studies that

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36 J.M. Malheiros et al. / Neuros

pecifically address the roles played by entorhinal cortex in painerception.

In light of the observations of Zhang et al. [30] and pain-relatedisruption in hippocampal memory encoding [9] findings and theotential importance of these results with respect to hippocampal-ntorhinal connections [27,28], more studies are now necessary toddress how these two cortical areas and their connections takeart in the neural substrate for pain-related memory encoding andmotional modulation in rodents and humans.

cknowledgement

This work was supported by FAPESP (Grant number: 09/53646-).

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