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Simon-Arceo K.,Laboratorio Of Neurofisiologia Integrativa | Contreras B.,Laboratorio Of Neurofisiologia Integrativa | Coffeen U.,Laboratorio Of Neurofisiologia Integrativa | Jaimes O.,Laboratorio Of Neurofisiologia Integrativa | Pellicer F.,Laboratorio Of Neurofisiologia Integrativa
Frontiers in Aging Neuroscience | Year: 2014

Some of the relevant factors that must be considered when dealing with old age include its growing numbers in the general population and pain contention in this age group. In this sense, it is important to study whether antinociceptive responses change with age. To elucidate this point, persistent pain in animals is the preferred model. In addition, the response to inflammatory pain in the same individual must be explored along its lifetime. Male Wistar rats were infiltrated with carrageenan (50 μl intraplantar) and tested 3 h and 24 h after injection using thermal (plantar test) and mechanociceptive tests (von Frey). The rats were divided into the following groups: a) young rats infiltrated for the first time at 12 weeks of age and re-infiltrated at 15 and 17 weeks, b) adult rats infiltrated for the first time at 28 weeks of age and re-infiltrated at 44 and 56 weeks, and c) old rats infiltrated for the first time at 56 weeks of age and re-infiltrated at 72 weeks. The rats tested for the first time at 12 and 56 weeks of age showed hyperalgesia due to carrageenan infiltration at 3 h and 24 h after injection. This result showed that old rats maintain the same antialgesic response due to inflammation. However, when the injection was repeated in the three age groups, the latency to the thermal and mechanociceptive responses at 3 h is increased when compared to animals exposed for the first time to inflammation. The response to thermal and mechanociception in old rats is the same as in young animals as long as the nociceptive stimulus is not repeated. The repetition of the stimulus produces changes compatible with desensitization of the response and evidences the significance of algesic stimulus repetition in the same individual rather than the age of the individual. © 2014 Simón-arceo, Contreras, Coffeen, León-olea, Jaimes and Pellicer.


de la Fuente-Sandoval C.,Instituto Nacional Of Neurologia Y Neurocirugia | Favila R.,General Electric | Pellicer F.,Laboratorio Of Neurofisiologia Integrativa | Graff-Guerrero A.,Multimodal Neuroimaging Schizophrenia Group
Psychiatry Research - Neuroimaging | Year: 2010

Clinical evidence suggests that there is decreased pain sensitivity in schizophrenia; however, the neurobiological mechanism of this decrease remains unknown. Using functional magnetic resonance imaging, we examined the blood oxygen level-dependent (BOLD) changes induced by experimental pain-tolerance (endure) hot stimuli vs. non-painful stimuli during an acute psychotic episode in 12 drug-free patients with schizophrenia and in 13 gender- and age-matched healthy controls. The analyses revealed that patients showed a greater BOLD response at S1 compared with controls but a reduced BOLD response in the posterior cingulate cortex (PCC), insula, and brainstem during pain-tolerance stimuli. Pain-tolerance temperature was higher in patients than in healthy controls. BOLD response in the insula positively correlated with unpleasantness and temperature in controls, but this effect was not observed in patients. S1 BOLD response positively correlated with unpleasantness in patients but not in controls. These initial results confirm that unmedicated patients with schizophrenia have a higher pain tolerance than controls, decreased activation in pain affective-cognitive processing regions (insula, PCC, brainstem), and an over-activation of the primary sensory-discriminative pain processing region (S1). These pilot results are the first to explore the mechanism driving altered pain sensitivity in schizophrenia. © 2010 Elsevier Ireland Ltd.


Coffeen U.,Laboratorio Of Neurofisiologia Integrativa | Coffeen U.,CINVESTAV | Manuel Ortega-Legaspi J.,Laboratorio Of Neurofisiologia Integrativa | Lopez-Munoz F.J.,CINVESTAV | And 4 more authors.
European Journal of Pain | Year: 2011

Injury to the insular cortex in humans produces a lack of appropriate response to pain. Also, there is controversial evidence on the lateralization of pain modulation. The aim of this study was to test the effect of insular cortex lesions in three models of pain in the rat. An ipsilateral, contralateral or bilateral radiofrequency lesion of the rostral agranular insular cortex (RAIC) was performed 48 h prior to acute, inflammatory or neuropathic pain models in all the experimental groups. Acute pain was tested with paw withdrawal latency (PWL) after thermal stimulation. Inflammation was induced with carrageenan injected in the paw and PWL was tested 1 h and 24 h afterwards. Neuropathic pain was tested after ligature of the sciatic nerve by measuring mechanical nociceptive response after stimulation with the von Frey filaments. Another model of neuropathy consisted of thermo stimulation followed by right sciatic neurectomy prior to the recording of autotomy behaviour. Acute pain was not modified by the RAIC lesion. All the RAIC lesion groups showed diminished pain-related behaviours in inflammatory (increased PWL) and neuropathic models (diminished mechanical nociceptive response and autotomy score). The lesion of the RAIC produces a significant decrease in pain-related behaviours, regardless of the side of the lesion. This is a clear evidence that the RAIC plays an important role in the modulation of both inflammatory and neuropathic - but not acute - pain. © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.


Ruiz Contreras A.E.,National Autonomous University of Mexico | Diaz M.M.,National Autonomous University of Mexico | Gomez B.P.,Laboratorio Of Neurofisiologia Integrativa | Romano A.,National Autonomous University of Mexico | And 2 more authors.
Salud Mental | Year: 2010

In this second paper of the Brain, Drugs and Genes review we would like to discuss illicit drugs and the genetics that may predispose subjects to addiction. We describe the effects, action sites and pathophysiological consequences of the use of these illicit drugs. The drugs that are reviewed are marijuana, heroin, cocaine, methamphetamine and 3,4-methylenedioxymethamphetamine or MDMA, also known as ecstasy. All of them cause an effect on the brain, modifying the activity of the neuronal systems, altering the activity or availability of the neurotransmitters or emulating their actions. The risk of dependence is related to the velocity with which these drugs induce plastic changes in the brain, very much like a learning process. Such changes underlie the patient's dependence to drugs. Therefore when a long term user quits and deprives the brain abruptly of these drugs, an abstinence syndrome is precipitated and it may be quite severe. Only for marijuana it seems to be mild, misleading people to believe this drug does not cause physical dependence. Marijuana (Cannabis sativa) is a plant which has its active principle Δ9-tetrahydrocannabinol (THC) in almost all its parts, i. e. the flowers, stems, seeds and leaves. It actually contains over 60 cannabinoids as well as other chemical compounds. Marijuana causes euphoria followed by relaxation and several other reinforcing effects. Among the adverse effects marijuana causes: alteration of short-term memory, slowness of reflexes, depression and anxiety, bronchitis and lung infections. Marijuana effects depend on the activation of the CB1 and CB2 receptors, distributed in the entire body. The CB1 receptor is mainly present in the brain. In medicine, Δ9-THC has been useful in treating symptoms caused by chemotherapy, and in treating the anorexia caused by the Acquired Immune Deficiency Syndrome. Also, an antagonist of the CB1 receptor, Rimonabant, has been used to treat morbid obesity with certain degree of success. However, despite this promising application of Rimonabant, the side effects it caused led to its withdrawal from the market in Europe, Canada and Mexico. Heroin, derived from morphine, which in turn is isolated from opium, causes euphoria and analgesia, suppresses hunger, increases energy and induces sleepiness. The adverse effects are liver and kidney diseases as well as a decrease in breathing and heart rates. This drug acts on the opioid receptors: MOR, DOR and KOR. Cocaine, derived from the coca plant (Erythroxylum coca) produces immediate rewarding effects that last between 30 to 60 min, and causes anxiety once its serum concentration drops. Due to its very short half-life, it is the most addictive of all drugs. Cocaine reduces hunger, thirst and sleep. The most used forms of cocaine are powder and crack (available as rock). The mechanism of action by which cocaine and related compounds induce their effects is the blockade of the dopamine transporter at the synapsis, leaving dopamine available for a longer time at the synapses of the motivation-reward system. Cocaine and related compounds induce blood vessel constriction, muscular spasm, chest pain, and an increase in heart rate and blood pressure, thus augmenting the risk of cardiac arrest and stroke. The methamphetamine, a synthetic stimulant, is a crystalline, odorless, bitter drug which causes a pleasant feeling and euphoria. Its action mechanism is the blockade of the dopamine transporter, same as cocaine. The effects pursued by the users of crystal methamphetamine are increased alertness, increase in physical activity and decrease in hunger. Its side effects include increase in body temperature, heart rate and blood pressure, thus augmenting the risk for stroke. Methamphetamine also triggers violent behavior, anxiety, irritability, confusion, paranoia and hallucinations. This compound has been used for medical reasons, such as in the treatment of narcolepsy and obesity. 3,4-methylenedioxymethamphetamine, MDMA or ecstasy, is a synthetic compound with stimulant and hallucinatory effects. Its action is exerted mainly on the serotonin transporter, leaving serotonin available at the synapsis for a longer time. After clearance from the bloodstream this drug causes severe depression. Ecstasy is also combined with other stimulants. All the drugs discussed here induce body changes that compromise the life of the user, or his health at the very least. Despite this fact, the highly reinforcing effects the drugs produce by over activating the motivation-rewarding system compel their repetitive use. Not all users, however, are equally vulnerable to becoming addicted or respond the same way to the use of drugs. The individual response depends, in part, on genetic factors, as we discuss in the following section. It is evident that not only environmental factors account for the vulnerability to addiction. Genetic factors also have a substantial contribution. In order to facilitate the understanding of the interaction environment-gene, we define the following concepts: gene, allele, mutation, polymorphism, heritability and epigenesis. Apparently, the genetic contribution to addiction vulnerability varies depending on the drug. For example, cocaine and opiates are much more dependant on genetic factors to trigger addiction than are nicotine, alcohol or marijuana. Mutations or polymorphisms carried by several genes might make the difference between being at high or low risk for addiction. They may also underlie the degree of response to rehabilitation treatments. Addiction, then, is a result of an interaction between environment and genes. Environmental demands make the organism modify its structure and physiology in order to cope efficiently to such demands. One crucial way to do so is by changing gene expression. Changes in gene expression may be a consequence of chemical rearrangements in the chromatin structure, which lead to transcriptional modifications that affect the expression of the proteins the genes encode. Consequently, the normal functions of such proteins in different systems are also altered. These adaptive rearrangements in the chromatin structure are called epigenesis. The epigenetic changes induced by environmental stimuli have been proved to affect the expression of several neurotransmitter receptors and trophic factors, among many other molecules crucial for the proper functioning of the Central Nervous System. Hence, these chromatin's structural changes, triggered by environmental demands, are most likely to help the subject cope with such specific demands. However, this adaptation is not free of charge, and requires a toll to be paid which is: vulnerability to addiction. Finally, one question arises: Who is the person most likely to seek a drug of abuse? Statistics have shown that those patients suffering from a psychiatric illness. This hypothesis suggests that addiction is a symptom or a disease caused by a psychiatric illness such as a personality disorder, depression or schizophrenia. Hence, at the end, drug addiction would be a co-morbid entity, generating what in Spanish we call the dual-disease. On the other hand, the self-medication hypothesis also makes sense, at least for an extensive group of patients. This hypothesis suggests that patients take drugs of abuse to relief the symptoms caused by their psychiatric pathology. The present review discusses the interaction between brain circuits, drugs and genes to generate an addict patient. We do not intend to revise each field exhaustively, but rather we intend to give the reader a general scenario on the convergence of these three worlds. Thus it may be better understood how addiction develops and how it may be treated.


Ortega-Legaspi J.M.,Laboratorio Of Neurofisiologia Integrativa | Ortega-Legaspi J.M.,Emory University | de Gortari P.,Laboratorio Of Neurofisiologia Molecular | Garduno-Gutierrez R.,Direccion de Neurociencias | And 4 more authors.
Molecular Pain | Year: 2011

Background: The anterior cingulate cortex (ACC) has been related to the affective component of pain. Dopaminergic mesocortical circuits, including the ACC, are able to inhibit neuropathic nociception measured as autotomy behaviour. We determined the changes in dopamine D1 and D2 (D1R and D2R) receptor expression in the ACC (cg1 and cg2) in an animal model of neuropathic pain. The neuropathic group had noxious heat applied in the right hind paw followed 30 min. later by right sciatic denervation. Autotomy score (AS) was recorded for eight days and subsequently classified in low, medium and high AS groups. The control consisted of naïve animals.A semiquantitative RT-PCR procedure was done to determine mRNA levels for D1R and D2R in cg1 and cg2, and protein levels were measured by Western Blot.Results: The results of D1R mRNA in cg1 showed a decrease in all groups. D2R mRNA levels in cg1 decreased in low AS and increased in medium and high AS. Regarding D1R in cg2, there was an increase in all groups. D2R expression levels in cg2 decreased in all groups. In cg1, the D2R mRNA correlated positively with autotomy behaviour. Protein levels of D2R in cg1 increased in all groups but to a higher degree in low AS. In cg2 D2R protein only decreased discretely. D1R protein was not found in either ACC region.Conclusions: This is the first evidence of an increase of inhibitory dopaminergic receptor (D2R) mRNA and protein in cg1 in correlation with nociceptive behaviour in a neuropathic model of pain in the rat. © 2011 Ortega-Legaspi et al; licensee BioMed Central Ltd.


De La Cruz-Aguilera D.L.,Instituto Nacional Of Neurologia Y Neurocirugia | Calleja J.,Instituto Nacional Of Neurologia Y Neurocirugia | Martinez A.,Laboratorio Of Neurofisiologia Integrativa | Morales-Espinoza G.,Instituto Nacional Of Neurologia Y Neurocirugia | And 2 more authors.
Archivos de Neurociencias | Year: 2011

Objectives: to evaluate the effect of cervical vagotomy on the weight of rats with and without cardiac puncture. Material and methods: eighty male Wistar rats, weighing 250-300 g were divided into four groups (n = 20). In rats from Group A, a midline incision of 2 cm in the anterior neck, identification and section of the vagus nerve were made; in those from Group B (sham), the vagus nerve was exposed, but it was no sectioned; the rats from Groups C (with cardiac puncture) and D (without cardiac puncture) were no operated (controls without surgical intervention). Then, all animals except those of the Group D, were blooded by cardiac puncture before the vagotomy and in the 21st post-operatory (PO) day. The weight of all rats was registered before making the vagotomy (day 0), everyday from the 1st to 7th, the 14th and the 21st PO days. The weight of vagotomized animals was significantly lower thanthat in non-vagotomized animals, only in the first PO day (p < 0.05). The weight of rats with and without cardiac puncture was similar. Conclusions: the cervical vagotomy associates to a loss of weight in rats, only in the first 24 h of the PO period. The cardiac puncture does not cause variations of weight in rats with or without vagotomy. ©INNN, 2011.


Coffeen U.,Laboratorio Of Neurofisiologia Integrativa | Ortega-Legaspi J.M.,Laboratorio Of Neurofisiologia Integrativa | Ortega-Legaspi J.M.,Emory University | de Gortari P.,Laboratorio Of Neurofisiologia Molecular | And 4 more authors.
Molecular Pain | Year: 2010

Background: The insular cortex (IC) receives somatosensory afferent input and has been related to nociceptive input. It has dopaminergic terminals and D1 (D1R) -excitatory- and D2 (D2R) -inhibitory- receptors. D2R activation with a selective agonist, as well as D1R blockade with antagonists in the IC, diminish neuropathic nociception in a nerve transection model. An intraplantar injection of carrageenan and acute thermonociception (plantar test) were performed to measure the response to inflammation (paw withdrawal latency, PWL). Simultaneously, a freely moving microdyalisis technique and HPLC were used to measure the release of dopamine and its metabolites in the IC. Plantar test was applied prior, one and three hours after inflammation. Also, mRNA levels of D1 and D2R's were measured in the IC after three hours of inflammation.Results: The results showed a gradual decrease in the release of dopamine, Dopac and HVA after inflammation. The decrease correlates with a decrease in PWL. D2R's increased their mRNA expression compared to the controls. In regard of D1R's, there was a decrease in their mRNA levels compared to the controls.Conclusions: Our results showed that the decreased extracellular levels of dopamine induced by inflammation correlated with the level of pain-related behaviour. These results also showed the increase in dopaminergic mediated inhibition by an increase in D2R's and a decrease in D1R's mRNA. There is a possible differential mechanism regarding the regulation of excitatory and inhibitory dopaminergic receptors triggered by inflammation. © 2010 Coffeen et al; licensee BioMed Central Ltd.


Ortega-Legaspi J.M.,Laboratorio Of Neurofisiologia Integrativa | Leon-Olea M.,Laboratorio Of Histologia Y Microscopia Electronica | De Gortari P.,Laboratorio Of Neurofisiologia Molecular | Amaya M.I.,Laboratorio Of Neurofisiologia Molecular | And 3 more authors.
European Journal of Pain | Year: 2010

The anterior cingulate cortex (ACC) and muscarinic receptors modulate pain. This study investigates changes in the expression of muscarinic-1 and -2 receptors (M1R, M2R) in rats' ACC (cg1-rostral- and cg2-caudal) using a model of neuropathic pain by denervation, measured as autotomy score (AS) for 8 days. Changes were analysed with painful stimuli and with scopolamine into the ACC prior to this scheme. We used reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence to determine M1R and M2R's mRNA and protein levels, respectively. Animals were divided in low, medium and high AS groups. Cg1 showed decreased mRNA levels for both M1R and M2R in the low AS group, as opposed to an increased expression in the medium and high AS groups. Both receptors correlated positively with AS in these groups. In the scopolamine-treated animals there was an increase in mRNA levels for both receptors in cg1, whereas in cg2, mRNA levels of M1R decreased in all the AS and scopolamine groups. The increased M2R mRNA in cg2 correlated with AS in the low, medium and high AS groups whereas all the scopolamine groups showed an increase. Immunoreactivity of the M2R in cg1 decreased in the medium AS group in comparison to controls but scopolamine treatment produced an increase in the medium scopolamine AS group compared to the medium AS group. The M1R in cg1 and both receptors in cg2 showed no immunoreactivity changes. These results highlight the role of the M2R in cg1 related to the degree of autotomy. © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.


PubMed | Laboratorio Of Neurofisiologia Integrativa
Type: | Journal: Molecular pain | Year: 2012

The anterior cingulate cortex (ACC) has been related to the affective component of pain. Dopaminergic mesocortical circuits, including the ACC, are able to inhibit neuropathic nociception measured as autotomy behaviour. We determined the changes in dopamine D1 and D2 (D1R and D2R) receptor expression in the ACC (cg1 and cg2) in an animal model of neuropathic pain. The neuropathic group had noxious heat applied in the right hind paw followed 30 min. later by right sciatic denervation. Autotomy score (AS) was recorded for eight days and subsequently classified in low, medium and high AS groups. The control consisted of nave animals.A semiquantitative RT-PCR procedure was done to determine mRNA levels for D1R and D2R in cg1 and cg2, and protein levels were measured by Western Blot.The results of D1R mRNA in cg1 showed a decrease in all groups. D2R mRNA levels in cg1 decreased in low AS and increased in medium and high AS. Regarding D1R in cg2, there was an increase in all groups. D2R expression levels in cg2 decreased in all groups. In cg1, the D2R mRNA correlated positively with autotomy behaviour. Protein levels of D2R in cg1 increased in all groups but to a higher degree in low AS. In cg2 D2R protein only decreased discretely. D1R protein was not found in either ACC region.This is the first evidence of an increase of inhibitory dopaminergic receptor (D2R) mRNA and protein in cg1 in correlation with nociceptive behaviour in a neuropathic model of pain in the rat.


PubMed | Laboratorio Of Neurofisiologia Integrativa
Type: Journal Article | Journal: European journal of pain (London, England) | Year: 2011

Injury to the insular cortex in humans produces a lack of appropriate response to pain. Also, there is controversial evidence on the lateralization of pain modulation. The aim of this study was to test the effect of insular cortex lesions in three models of pain in the rat. An ipsilateral, contralateral or bilateral radiofrequency lesion of the rostral agranular insular cortex (RAIC) was performed 48h prior to acute, inflammatory or neuropathic pain models in all the experimental groups. Acute pain was tested with paw withdrawal latency (PWL) after thermal stimulation. Inflammation was induced with carrageenan injected in the paw and PWL was tested 1h and 24h afterwards. Neuropathic pain was tested after ligature of the sciatic nerve by measuring mechanical nociceptive response after stimulation with the von Frey filaments. Another model of neuropathy consisted of thermo stimulation followed by right sciatic neurectomy prior to the recording of autotomy behaviour. Acute pain was not modified by the RAIC lesion. All the RAIC lesion groups showed diminished pain-related behaviours in inflammatory (increased PWL) and neuropathic models (diminished mechanical nociceptive response and autotomy score). The lesion of the RAIC produces a significant decrease in pain-related behaviours, regardless of the side of the lesion. This is a clear evidence that the RAIC plays an important role in the modulation of both inflammatory and neuropathic - but not acute - pain.

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