Plasticity of the somatosensory system and its involvement in chronic pain


The somatosensory system is the anatomical and physiological neural substrate for detecting mechanical deformations of the skin, muscles, joints and other deep organs, conveying and processing that information through a number of pathways and neural centers, and eventually providing higher brain centers with the information needed to generate conscious perception of somatic sensations. Peripheral stimuli are transformed into neural impulses at the sensory receptors, and these impulses are conveyed through peripheral nerves to the dorsal horn of spinal cord and the dorsal column nuclei and trigeminal nuclei in the brain stem. The second processing station is the ventral posterior nuclear complex of the thalamus, from which the somesthetic information reaches the cerebral cortex. The whole system displays an exquisite spatial oganization, which is reflected in a topologically continuous (somatotopical) arrangement of neuronal and axonal populations, with separate or intertwined "channels" specialized to convey and process different sensory submodalities. Representational "maps" arising from this anatomical and functional order, first described early in the XXth century, have been shown since the late 1970's to be anything but rigid and immutable, even in adult and aging individuals. Changes in these maps and in the underlying neural structures and circuits can be brough about by learning, experience, trauma, disease, or experimental manipulation of sensory organs, nerves or centers. and are accompanied by a host of cytological changes that reflect alterations in gene expression and metabolic activities imposed by the altered input.

A practical adjunct of the knowledge derived from studying brain plasticity is a better understanding of the processes involved in the reaction of the neural structures to injury and disease, and the ability to design new therapeutic approaches applicable in the human and veterinary clinical settings. Agents and maneuvers intended to compensate for or repair structural and functional losses should take into account the possibilities, limits and characteristics of neural plasticity in normal and altered conditions, and their effects can now be assessed at molecular, anatomical, electrophysiological and behavioral levels. One such a reactive condition, which may result from disorders of the peripheral or central nervous system, is chronic pain, a cause of prime medical, social and economic concern in developed countries. Its treatment poses a greater challenge than acute pain, particularly when pain originates in nerve lesions, in what is known as neuropathic pain. Neuropathic pain syndromes of peripheral origin are common in clinical practice, and include painful conditions that accompany diabetes, cancer, and ischemia, post-amputation, post-deafferentation and phantom pain, and neuralgias of various kinds, in particular postherpetic and craniofacial.

Amongst the painful conditions in the craniofacial territory, apart from dental pain and temporomandibular disorders, migraine and trigeminal neuralgia are most prominent, followed by cluster headache, atypical facial pain, and other facial neuralgias. These disorders are difficult to treat and their pathophysiology is harder to examine, because of the anatomical and functional complexities of the nerves and territories affected. Moreover, few animal models have been developed specifically for studying migraine and trigeminal pain, largely due to technical difficulties, and this is partly responsible for the limited current knowledge of the pathophysiology of craniofacial pain conditions. Yet, the same four basic mechanisms involved in the generation and maintenance of neuropathic pain in general are likely to underlie this process in the trigeminal territory: peripheral sensitization (due to changes in excitability of peripheral nerve fibers), central sensitization (due to an imbalance in neurotransmitters and receptors in the spinal cord and brain stem), reorganization of afferents, local neuronal circuits and glia (in sensory ganglia, spinal cord and brain stem), and attenuation or loss of inhibitory mechanisms (in local circuits and descending modulatory connections). An understanding of these mechanisms and processes is essential to define new therapeutic targets and assess the value of those being used.

Specific research lines

Stability and mutability of ganglion cell populations in adult rats

Sensory input-dependent plasticity of specific cell populations of the mature trigeminal sensory system

Neural bases and mechanisms of chronic cephalic pain conditions


In vivo electrophysiological recordings -- Surgery of laboratory mammals -- Somatic sensory and motor behavioral testing of rodents -- Neuronal labeling using neural tracers and viral transduction -- Histology, Histochemistry and Immunohistochemistry -- Digital neuron reconstruction -- Confocal and electron microscopy -- Stereology



Faculty and researchers:

Graduate students:

  • Julia Fernandez-Montoya, BS
  • Laura Vazquez, BS
  • Luke Diekhorst (Internship from Radboud University, The Netherlands)

Associated researchers:

  • Francisco Clascá, MD, PhD (UAM, Madrid)
  • Angel Nuñez, PhD (UAM, Madrid)
  • Alfonso Lagares, MD,PhD (Hospital Universitario 12 de Octubre, Madrid)
  • Javier Egea, PhD (Hospital Universitario La Princesa, Madrid)
  • José M. García-Verdugo, PhD (Universidad de Valencia)
  • Vicente Herranz-Perez, PhD (Universidad de Valencia)
  • Jose A. Villacorta, PhD (Universidad Complutense, Madrid)

Technical Assistants:

  • Begoña Rodríguez


Selected publications

  • Last five years:
  1. Lorena Sanz, Silvia Murillo-Cuesta, Pedro Cobo, Rafael Cediel-Algovia, Julio Contreras,Teresa Rivera, Isabel Varela-Nieto and Carlos Avendaño. Swept-sine noise-induced damage as a hearing loss model for preclinical assays
    Front Aging Neurosci., 2015, doi: 10.3389/fnagi.2015.00007
  2. Martin, Y. B., Negredo, P., Villacorta-Atienza, J. A., and Avendano, C. Trigeminal intersubnuclear neurons: morphometry and input-dependent structural plasticity in adult rats.
    J.Comp Neurol. 2014, 522:1597-1617.
  3. Herrera-Rincon C, Torets C, Sanchez-Jimenez A, Avendaño C, Panetsos F. Chronic electrical stimulation of transected peripheral nerves preserves anatomy and function in the primary somatosensory cortex.
    Eur J Neurosci. 2012 Dec;36(12):3679-3690.
  4. Krzyzanowska A, Avendaño C. Behavioral testing in rodent models of orofacial neuropathic and inflammatory pain.
    Brain Behav. 2012 Sep;2(5):678-697.
  5. Blesa J, Pifl C, Sánchez-González MA, Juri C, García-Cabezas MA, Adánez R, Iglesias E, Collantes M, Peñuelas I, Sánchez-Hernández JJ, Rodríguez-Oroz MC, Avendaño C, Hornykiewicz O, Cavada C, Obeso JA. The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study.
    Neurobiol Dis. 2012 Oct;48(1):79-91.
  6. Agnieszka Krzyzanowska, Silvia Pittolo, Marina Cabrerizo, Jorge Sánchez-López, Senthil Krishnasamy, César Venero, Carlos Avendaño. Assessing nociceptive sensitivity in mouse models of inflammatory and neuropathic trigeminal pain.
    J. Neurosci. Meth. 2011; 201:46-54.
  7. Herrera-Rincon C, Torets C, Sanchez-Jimenez A, Avendaño C, Guillen P, Panetsos F. Structural preservation of deafferented cortex induced by electrical stimulation of a sensory peripheral nerve.
    Conf Proc IEEE Eng Med Biol Soc. 2010:5066-9.
  8. Rivera-Arconada I, Benedet T, Roza C, Torres B, Barrio J, Krzyzanowska A, Avendaño C, Mellström B, Lopez-Garcia JA, Naranjo JR. DREAM regulates BDNF-dependent spinal sensitization.
    Mol Pain.18;6:95-109 (2010).
  9. Yasmina Martin ,Carlos Avendaño, Maria Jose Piedras & Agnieszka Krzyzanowska. Evaluation of Evans Blue extravasation as a measure of peripheral inflammation.
    Nature Protocol Exchange, doi:10.1038/protex.2010.209 (2010).
  10. Porrero,C.; Rubio-Garrido,P.; Avendaño,C.; Clasca,F. Mapping of fluorescent protein-expressing neurons and axon pathways in adult and developing Thy1-eYFP-H transgenic mice.
    Brain Res., 1345:59-72 (2010).
  11. Yasmina B. Martin, Eduardo Malmierca, Carlos Avendaño, Angel Nuñez. Neuronal disinhibition in the trigeminal nucleus caudalis in a model of chronic neuropathic pain.
    Eur. J. Neurosci., 32:399-408 (2010).
  12. Alfonso Lagares, Juan Jose Rivas, Luis Jiménez, Marta Cicuéndez, Carlos Avendaño. Central demyelination in the pathogenesis of trigeminal neuralgia associated with cerebellopontine angle tumors: case report with ultrastructural trigeminal root analysis.
    Neurosurgery 66:E841-E842 (2010) - selected as “Editor Choice” in the Journal:
  • Earlier relevant publications:
  1. P. Negredo, Y. B. Martin, A. Lagares, J. Castro, J. A. Villacorta, C. Avendaño. Trigeminothalamic barrelette neurons: natural structural side asymmetries and sensory input-dependent plasticity in adult rats. Neuroscience, 163:1242–1254 (2009) .
  2. Yasmina B Martin, Carlos Avendaño. Effects of removal of dietary polyunsaturated fatty acids on plasma extravasation and mechanical allodynia in a trigeminal neuropathic pain model. Molecular Pain, 5:8-17 (2009)
  3. Jorge Castro, Pilar Negredo, Carlos Avendaño. Fiber composition of the rat sciatic nerve and its modification during regeneration through a sieve electrode. Brain Res., 1190:65-77 (2008)
  4. Fivos Panetsos, Carlos Avendaño, Pilar Negredo, Jorge Castro, Vanessa Bonacasa. Neural prostheses: electrophysiological and histological evaluation of Central Nervous System alterations due to long-term implants of sieve electrodes to peripheral nerves in cats. Transactions on Neural Systems & Rehabilitation Engineering, 16:223-232 (2008)
  5. Alfonso Lagares, Hong-Yun Li, Xin-Fu Zhou, Carlos Avendaño. Primary Sensory Neuron Addition in the Adult Rat Trigeminal Ganglion: Evidence for Neural Crest Glio-Neuronal Precursor Maturation. J. Neuroscience, 27:7939 –7953 (2007)
  6. Raquel Machín; César G. Pérez-Cejuela; Roger Bjugn; Carlos Avendaño. Effects of long-term sensory deprivation on asymmetric synapses in the whisker barrel field of the adult rat. Brain Res. 1107:104-110 (2006).
  7. Isla A, Martinez JR, Perez Lopez C, Perez Conde C, Morales C, Avendano C. Anatomical and functional connectivity of the transected ulnar nerve after accessory nerve neurotization in the cat. J Neurosurg Sci. 50:33-40 (2006).
  8. Panetsos F, Nuñez A, Avendaño C.  Oscillations in the lower stations of the somatosensory pathway. Lecture Notes in Computer Science 1606:206-210 (2006)
  9. C. Avendaño, R. Machín, P. E. Bermejo, A. Lagares. Neuron numbers in the trigeminal nuclei of the rat: A GABA- and Glycine-immunocytochemical and stereological analysis. J. Comp. Neurol. 493:538-553 (2005)
  10. Bermejo,P.E.; Jimenez,C.E.; Torres,C.V.; Avendano,C. Quantitative stereological evaluation of the gracile and cuneate nuclei and their projection neurons in the rat. J. Comp. Neurol. 463:419-433 (2003)
  11. Negredo, P.; Castro, J.; Lago, N.; Navarro, X.;  Avendaño, C. Differential growth of axons from sensory and motor neurons through a regenerative electrode: a stereological, retrograde tracer, and  functional study in the rat.
    Neuroscience, 128:605–615 (2004)
  12. Raquel Machín, Beatriz Blasco, Roger Bjugn, Carlos Avendaño. The size of the whisker barrel field in adult rats: minimal nondirectional asymmetry and limited modifiability by chronic changes of the sensory input.
    Brain Res. 1025:130-138 (2004).
  13. Lagares, A.; Avendaño, C. Lateral asymmetries in the trigeminal ganglion of the male rat. Brain Res., 865:202-210 (2000)
  14. Núñez, A.; Panetsos, F.; Avendaño, C. Rhythmic neuronal interactions and synchronization in the rat dorsal column nuclei. Neuroscience 100:599-609 (2000)
  15. Isla, A.; Bejarano, B.; Morales, C.; Pérez Conde, C,; Avendaño, C. Anatomical and functional connectivity of the transected ulnar nerve after intercostal neurotization in the cat. J. Neurosurg., 90:1057-1063 (1999)
  16. Lagares, A.; Avendaño, C. An efficient method to estimate cell number and volume in multiple dorsal root ganglia. Acta Stereologica, 18:185-195 (1999)
  17. Panetsos, F.; Nuñez, A.; Avendaño, C. Sensory information processing in the dorsal column nuclei by neuronal oscillators. Neuroscience 84:635-639 (1998)
  18. Panetsos, F.; Núñez, A.; Avendaño, C. Electrophysiological effects of temporary deafferentation on two characterized cell types in the nucleus gracilis of the rat. Eur. J. Neurosci. 9:563-572 (1997).
  19. Avendaño, C.; Dykes, R.W. Evolution of morphological and histochemical changes in the adult cat cuneate nucleus following forelimb denervation. J. Comp. Neurol., 370:479-490 (1996).
  20. Avendaño, C.; Dykes, R.W. Quantitative analysis of anatomical changes in the cuneate nucleus following forelimb denervation: a stereological morphometric study in adult cats. J. Comp. Neurol., 370:491-500 (1996)
  21. Avendaño, C.; Lagares, A. A stereological analysis of the numerical distribution of neurons in the dorsal root ganglia C4-T2 in adult macaque monkeys. Somatosens. Mot. Res., 13:59-66 (1996)
  22. Avendaño, C.; Umbriaco, D.; Dykes, R.W.; Descarries, L. Acetylcholine innervation of sensory and motor neocortical areas in adult cat: a choline acetyltransferase immunohistochemical study. J. Chem. Neuroanat. 11:113-130 (1996)
  23. Panetsos, F.; Núñez, A.; Avendaño, C.  Local anaesthesia induces immediate receptive field changes in nucleus gracilis and cortex.  Neuroreport 7:150-152 (1995)   
  24. Avendaño, C.; Umbriaco, D.; Dykes, R.W.; Descarries, L. Decrease and long-term recovery of choline acetyltransferase immunoreactivity in adult cat somatosensory cortex after peripheral nerve transections. J. Comp. Neurol., 354:321-332 (1995) 
  25. Dykes, R.W.; Avendaño, C.; Leclerc, S.S.  Evolution of cortical responsiveness subsequent to multiple forelimb nerve transections: an electrophysiological study in adult cat somatosensory cortex. J. Comp. Neurol., 354:333-344 (1995)