Insular cortex lesion diminishes neuropathic and inflammatory pain-like behaviours

European Journal of Pain 15 (2011) 132–138

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Insular cortex lesion diminishes neuropathic and inflammatory pain-like behaviours Ulises Coffeen a,b, J. Manuel Ortega-Legaspi a, Francisco J. López-Muñoz b, Karina Simón-Arceo a, Orlando Jaimes a, Francisco Pellicer a,* a b

Laboratorio de Neurofisiología Integrativa, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría ‘‘Ramón de la Fuente”, México DF, Mexico Departamento de Farmacobiología, Cinvestav-Sede Sur, México DF, Mexico

a r t i c l e

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Article history: Received 24 February 2010 Received in revised form 27 May 2010 Accepted 6 June 2010 Available online 8 July 2010 Keywords: Insular cortex Pain Nociception Lesion

a b s t r a c t 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. Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

1. Introduction The importance of the insular cortex related to pain processing was historically documented in two clinical entities. The first one is asymbolia for pain syndrome which is characterized by a lack of appropriate motor and emotional responses to painful stimuli. This syndrome is caused by a disconnection of sensory input to the limbic system provoked by an injury to the insular cortex (Berthier et al., 1988; Augustine, 1996). The second clinical entity is the pseudothalamic pain syndrome, in which patients develop spontaneous hemi-body pain. This syndrome is attributed to an interruption of pathways between the insular cortex and the dorsal thalamus (Schmahmann and Leifer, 1992). Furthermore, electrical stimulation of the posterior insular cortex in patients with temporal lobe epilepsy elicits painful sensations (Ostrowsky et al., 2002; Afif et al., 2008; Mazzola et al., 2009). Moreover, a lesion on the opercular insular cortex can im-

* Corresponding author. Address: Instituto Nacional de Psiquiatría ‘‘Ramón de la Fuente”, Calzada México-Xochimilco 101, San Lorenzo Huipulco, Tlalpan, CP 14370, México DF, Mexico. Fax: +52 (55) 5655 99 80. E-mail address: [email protected] (F. Pellicer).

pair pain perception in restricted body areas (Greenspan et al., 1999; Bowsher et al., 2004). Acute, sub-acute and chronic painful stimulation have shown that the insular cortex is activated, as demonstrated with functional imaging studies (Coghill et al., 1994; Ploghaus et al., 1999; Hofbauer et al., 2001; Peyron et al., 2004; Lorenz and Casey, 2005). Moreover, functional magnetic resonance imaging studies in rats show pain matrix activation, including the insular cortex, in response to electrical and chemical nociceptive input as well as with acute and chronic pain (Tuor et al., 2000; Hess et al., 2007; Endo et al., 2008; Shih et al., 2008a,b; Westlund et al., 2009). Animal studies performed in the rostral agranular insular cortex (RAIC) show that it is an important locus that receives somatic afferences and has been related to nociceptive input (Jasmin et al., 2004; Coffeen et al., 2008; Alvarez et al., 2009). However, the type of nociceptive trigger that activates this region is not fully understood. As described in humans (Merskey and Watson, 1979; Hsieh et al., 1996; Coghill et al., 2001; Brooks et al., 2002; Lugo et al., 2002; Youell et al., 2004; Symonds et al., 2006), there is also experimental evidence in rodents that suggests lateralization in the modulation of nociceptive input. However, experimental evidence of the dominance of pain control is controversial. Left hemispheric lateralization was shown using unilateral cortex inactivation and

1090-3801/$36.00 Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2010.06.007

U. Coffeen et al. / European Journal of Pain 15 (2011) 132–138

then measuring pain induced vocalisations (Bianki and Snarskii, 1988). In contrast, dominance of the right temporal lobe amygdala was suggested after inducing injury and measuring the expression of extracellular signal-regulated kinase in the central nucleus of the amygdala (Carrasquillo and Gereau, 2008). The aim of this study was to test if the lesion (contralateral, ipsilateral or bilateral to nociceptive input) of the RAIC can modify

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pain-like behaviours in different models of acute, inflammatory and neuropathic pain. 2. Material and methods Experiments were conducted in agreement with the ethics committee regulations of the International Association for the

Fig. 1. Histological verification of RAIC lesions. (A) Coronal slice of the rat’s brain (1.0 anterior from bregma) that shows the position of bilateral RAIC’s lesions (black arrows). An image from the atlas by Paxinos and Watson (1998) was superimposed to the left side of the brain in order to make evident the exact localisation of the lesion site. (B) Left side of the brain that shows an example of an off-site lesion (red arrow). The image of the atlas shows, in red dots, the position of various off-site lesions found in the experiment. The animals, where off-site lesions were found, were dropped out from the ‘‘n” in the corresponding group.

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(1994). Briefly, light mechanical stimuli using sufficient force to cause slight buckling of the filament was applied to the plantar surface of the foot using different strengths of von Frey filaments (Stoelting, Woodale, IL, USA). Filaments with incremental stiffness (1–15 g) were applied to the right paw in a series in ascending order (1, 4, 10 and 15 g). Brisk foot withdrawals in response to normally innocuous mechanical stimuli were considered positive and expressed as a percentage. The procedure was repeated ten times for each filament. In order to determine the threshold between allodynia and hyperalgesia a naïve group was tested (without RAIC’s lesion or electrode placement and loose ligatures). This threshold was established at 15 g. The number of animals in each group for this model (sham, naïve, contralateral, ipsilateral and bilateral) was eight.

Study of Pain (Zimmermann, 1983) and with our institution’s projects and bioethics commission’s approval. Male Wistar rats (250–300 g) were raised, housed and maintained in our institution’s animal house. During the observation period the animals were kept in individual, transparent acrylic cages, with light–dark cycles of 12  12 h at 23 °C and 52% humidity, and with ad libitum feeding and hydration. For all surgical procedures, the rats were anaesthetized with a mixture of isofluorane 2% and O2 98%. 3. RAIC lesion Under general anaesthesia, a bipolar electrode (Blunt steel, Stoelting Co.) connected to an Ugo Basile 3500 Lesion Making Device was stereotaxically positioned in the RAIC (coordinates A: 1.0 from bregma, L: ±4.5 and H: 6 mm from the meninges). The radiofrequency lesion was carried out at 0.5 mA during 10 s. This procedure was done in the following groups: (A) ipsilateral, (B) contralateral or (C) bilateral to its nociceptive experimental model. Finally, a sham group was performed (the electrode was positioned in the RAIC but the lesion was not executed) for each animal model of pain. The lesion was performed 48 h prior to every model used in this study.

4.3. Neuropathic pain model (neurectomy) The nociceptive process was induced under general anaesthesia by immersing the rat’s right hind paw in hot water at 55 °C for 20 s (Coderre and Melzack, 1986). The animal remained anaesthetised for 30 min afterwards when a right sciatic denervation was carried out. Briefly, the right sciatic nerve was exposed, cut and ligated with silk 3–0 suture. Five millimeters of the distal end were removed in order to avoid reinervation. Skin was closed with silk 3–0 suture. The number of animals used was 9 for the bilateral and contralateral lesion groups, 16 for the ipsilateral and 10 for the sham group. In both models of neuropathic pain only a bilateral sham group was used as a control given that in the acute and inflammatory models there were no differences within the sham groups. This allowed us to minimise the number of animals used. After the surgical procedure, autotomy behaviour (AB) was analysed. Briefly, daily autotomy scores were computed for 25 days using a previously devised scale (Wall et al., 1979). This scale gives a score of 1 for the removal of one or more nails; an additional score of 1 was added for each distal half digit attacked and a further score of 1 was added for each proximal half digit attacked. If the distal or proximal half of the paw was attacked, an additional score of 1 was added for each. We also recorded the AB onset as the mean day, within each group, in which autotomy initiated. In addition, the number of animals that presented AB per group was measured (incidence). On day 25, animals were sacrificed by an overdose of pentobarbital and denervation was verified.

4. Animal models of pain 4.1. Acute and Inflammatory models An inflammatory process was induced by the infiltration in the right hind paw of carrageenan lambda (Sigma Chemical Co. St. Louis MO, USA, CAR 1% in saline solution, 250 ll). After 5 days of habituation to the testing equipment and personnel (10 min/ day), thermonociceptive response was measured in a Plantar Test Apparatus (Ugo Basile mod. 7370). Paw withdrawal latency (PWL) was determined to the nearest 0.1 s using the device’s electronic clock. All groups (n = 10 for sham, n = 9 for the bilateral and ipsilateral groups, and n = 7 for the contralateral group) had the thermonociceptive test performed prior to the induction of inflammation in order to test the nociceptive threshold (acute pain). PWL was also determined after 1 and 24 h following the induction of the inflammatory process which induces hyperalgesia. 4.2. Neuropathic pain model (chronic constriction injury)

5. RAIC lesion histological verification

Under general anaesthesia, the right sciatic nerve was dissected and exposed. Proximal to the sciatic trifurcation, four loose ligatures (5.0 Ethicon chromic catgut) were placed around the nerve (Bennett and Xie, 1988). Ten days after surgery, pain-like behaviour was measured using the von Frey filaments with the method described by Chaplan et al.

At the end of each experiment, the site of the lesion was verified. Briefly, the animals were intracardially perfused with physiological saline solution, followed by 10% formaldehyde. Brains were allowed to postfix for 2 days and cut in 40 lm coronal slices that

Table 1 Paw withdrawal latency (PWL, expressed in seconds ± standard error) to thermal stimulation in the three RAIC’s lesion groups given acutely, 1 and 24 h after inflammation. There is an increased PWL in all the RAIC lesion groups 1 and 24 h after the induction of inflammation with carrageenan in the right hind paw (Student’s t-test, t and p values shown in the table). When tested under acute thermal stimulation, PWL showed no difference between the RAIC lesion groups and the sham.

Bilateral lesion

Acute thermal stimulation (s)

1 h after inflammation (s)

24 h after inflammation (s)

Sham

Lesion

Sham

Lesion

Sham

Lesion

9.1 ± 0.7

9.4 ± 0.4

3.2 ± 0.3

7.0 ± 0.9

5.6 ± 0.2

8.2 ± 0.9

t = 5.358, p < 0.001 Contralateral lesion

6.0 ± 0.4

7.1 ± 0.6

3.9 ± 0.4 t=

Ipsilateral lesion

7.5 ± 0.4

7.8 ± 0.5

5.7 ± 0.5

2.432, p = 0.029

3.9 ± 0.6 t=

t = 3.964, p = 0.001

2.970, p = 0.012

3.4 ± 0.3 t=

7.0 ± 0.6

4.1 ± 0.3 t=

6.0 ± 0.3

4.798, p < 0.001

3.209, p = 0.001

6.4 ± 0.5

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were immediately placed on a glass slide and digitalised in a scanner (HP Scanjet 5550C). The images were analysed by comparing them to an anatomical atlas (Paxinos and Watson, 1998) (Fig. 1).

no differences. The naïve group did not present a response to stimulation with 1, 4 and 10 g filaments and it showed no difference in the response to the 15 g filament when compared to the RAIC lesion groups.

5.1. Statistical analysis 6.3. Neuropathic pain model (neurectomy)

6.1. Acute and inflammatory models The results showed that the lesion of the RAIC increases PWL after the injection of carrageenan in all the experimental groups compared to its sham: ipsilateral lesion 79% at 1 h, 56% at 24 h; contralateral lesion 46% at 1 h, 76% at 24 h; and bilateral lesion 118% at 1 h, 46% at 24 h (for raw PWL values in seconds and statistical details refer to Table 1). With regard to nociceptive threshold testing (prior to carrageenan), there were no differences between groups compared to the sham (Fig. 2). The histological verification showed that in the animals with off-site lesions (PWL, 3.7 ± 0.8 s) there were no differences when compared to the sham group (PWL, 3.9 ± 0.4 s; Fig. 1B). Those brains where the lesion was considered off-site were dropped from the group and therefore not included in the statistical analysis. 6.2. Neuropathic pain model (chronic constriction injury) All the RAIC lesion groups showed a decrease in mechanical nociceptive response compared to the sham group when tested with von Frey filaments. With the 1 g filament, the three groups with RAIC lesions decreased mechanical response (ipsilateral, 2.5%; contralateral, 2.5%; and bilateral, 0%) when compared to sham (17.1%; one-way ANOVA, F = 12.628, p < 0.001; Fig. 3A). With regard to the 4 g von Frey filament, the results followed the same pattern: sham 40%, ipsilateral 12.5%, contralateral 10%, bilateral 10% (one-way ANOVA, F = 5.357, p < 0.001; Fig. 3B). A similar decrease in the groups with lesions was seen with the 10 g filament: sham 57.1%, ipsilateral 20%, contralateral 20%, bilateral 20% (oneway ANOVA, F = 10.379, p < 0.001; Fig. 3C); and also with the 15 g one (sham 77.1%, ipsilateral lesion 30%, contralateral lesion 32.5%, bilateral lesion 30%; one-way ANOVA, F = 5.797, p < 0.001; Fig. 3D). The comparison within all the RAIC lesion groups showed

BILATERAL

Paw Withdrawal Latencies (s)

(A) 12

Acute thermal Stimulation

1 h after inflammation

24 h after inflammation

10

* **

8 6 4 2 0

Sham

Lesion

Sham

Lesion

Sham

Lesion

CONTRALATERAL

(B) Paw Withdrawal Latencies (s)

6. Results

All the RAIC lesion groups (regardless of the side of the lesion) showed a decrease in autotomy scores compared to the sham

9

Acute thermal Stimulation

8

1 h after inflammation

7

24 h after inflammation

**

*

6 5 4 3 2 1 0

Sham

Lesion

Sham

Lesion

Sham

Lesion

IPSILATERAL

(C) Paw Withdrawal Latencies (s)

In the acute and inflammatory models, the differences in PWL between the sham and each experimental group were established by a Student’s t-test. In the neuropathic pain model by chronic constriction injury, the differences between groups were established with a variance analysis (one-way ANOVA) and a Tukey as a post hoc test. In the neuropathic pain model by neurectomy the following variables in all groups were calculated from the raw data obtained from the daily records of autotomy: score, incidence (calculated as the number of rats that showed the behaviour in relation to the total number of animals in that group), the onset of the behaviour (calculated as the mean day of onset of the behaviour for every group) and its maximum score (calculated as the sum of the autotomy scores for every group considering the autotomy 13 score categorization (Wall et al., 1979). In order to analyse the evolution of the autotomy score a repeated measures ANOVA was used to establish the differences between groups and a one-way ANOVA with a Tukey test as a post hoc was used to establish on which days and which groups were different. AB onset data were analysed by means of also a one-way ANOVA. Differences in the percentage of subjects showing AB per treatment (incidence) were assessed by means of a Fisher exact probability test. Significance for all statistical analyses was established at p < 0.05.

10

Acute thermal Stimulation

9

1 h after inflammation

8

24 h after inflammation

*

**

7 6 5 4 3 2 1 0

Sham

Lesion

Sham

Lesion

Sham

Lesion

Fig. 2. Attenuation of carrageenan induced thermal hyperalgesia by selective lesion of the insular cortex. Thermal hyperalgesia was induced by intraplantar injection of carrageenan (250 ll, 1%) in sham rats (n = 10) or in rats subjected to bilateral (A, n = 9), contralateral (B, n = 7 ) or ipsilateral (C, n = 9) lesions of the insular cortex. Laterality is considered with reference to the injected hind paw. Carrageenan injection produced significant decrease in PWL in sham rats and this decrease was significantly attenuated by various insular lesions. Each bar represents the average of PWL measurements (expressed in seconds) done on a separate group of rats at the indicated time interval. The value of significance of differences was established with reference to the corresponding measurements on sham rats (Student’s t-test: * p < 0.05, **p < 0.001).

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groups (repeated measures ANOVA F = 14.125, p < 0.001). The bilateral lesion group showed a decrease of 55% at day 25 (the last day of data recording and maximum autotomy score) compared to the sham whereas the contralateral group decreased 39% and the

(A)

25

ipisilateral 35%. The bilateral lesion group shows a significant decrease in autotomy score from day 4 to 25, the ipsilateral from day 5 to 25 and the contralateral from day 9 to 25, all compared to the sham group (one-way ANOVA, F = 12.820, p < 0.001, Tukey

(B)

40 35

% of response

% of response

20

45

15 10

30 25 20 15 10

5

5 0

(C)

Sham

Naive

0

Bilateral Contralateral Ipsilateral

(D)

70

Bilateral Contralateral Ipsilateral

Sham

Naive

Bilateral Contralateral Ipsilateral

90

70

50

% of response

% of response

Naive

80

60

40 30 20

60 50 40 30 20

10 0

Sham

10 Sham

Naive

0

Bilateral Contralateral Ipsilateral

Fig. 3. Response (expressed as percentage and standard error) to mechanical stimulation with von Frey filaments in the right hind paw after the use of the chronic constriction injury model of the right sciatic nerve. All the RAIC lesion groups show a diminished percentage response in the (A) 1, (B) 4, (C) 10 and (D) 15 g filaments stimulation. Also, notice that the naïve group shows no response with the 1, 4, and 10 g filaments and shows no difference when compared to the RAIC lesion groups when tested with the 15 g filament.

Sham Bilateral Lesion

12

Contralateral Lesion Ipsilateral Lesion

Autotomy score

10

8

6

4

2

0 1

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Days Fig. 4. Behavioural nociceptive response measured as autotomy score along 25 days in groups with thermonociception followed by denervation with bilateral, contralaleral, or ipsilateral RAIC lesions. All the RAIC lesion groups showed a decreased autotomy score when compared to the sham group. The days which are depicted in red are those in which the difference with the sham group is statistically significant (one-way ANOVA with a Tukey test as a post hoc, p < 0.05).

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post hoc p < 0.05; Fig. 4). The onset and incidence of autotomy behaviour showed no differences between the RAIC lesion groups and sham group.

7. Discussion This study highlights the role of the rostral agranular insular cortex in pain-like behaviours. The lesion of this structure did not alter nociceptive thresholds in sham animals, but it decreased hyperalgesia and allodynia in the different models for inflammatory and neuropathic pain. The nociceptive test used in each model of pain was chosen on the basis of maximum sensitivity. In the acute and inflammatory models, we tested nociception by applying a thermal stimulus. This allowed testing acute pain and inflammatory pain (hyperalgesia) with the same kind of stimulation. The chronic constriction injury model using the von Frey filaments tested both hyperalgesia and allodynia, which could not have been measured if we had used thermonociception (Hargreaves et al., 1988; Vissers et al., 2003). In the model in which acute nociceptive thresholds were measured, the lesion shows that the RAIC is not directly involved in the modulation of acute anti-nociceptive reflexes. This may be in part because this process is mainly modulated in the spinal cord (Willis and Coggeshall, 1991), and the spinal cord dorsal horn mediates the transmission of nociceptive information with antialgesic reflexes (Wall, 1980; Willis, 1988). With regard to the inflammation model, we tested the process after 1 and 24 h from its induction. This allows analysis of the results from two different points of view. The first is related to temporality, since inflammation is a sub-acute process involving from hours to days. The second is related to the supraspinal structures involved in the processing of an inflammatory sub-acute process. The role played by the RAIC in the modulation of inflammatory pain behaviour is clearly seen in this study. Interestingly, inflammatory responses can be modified by the experimental manipulations of other supraspinal structures which, along with the RAIC, belong to the pain matrix. In this line of evidence, the electrical stimulation of the ventral tegmental area diminishes whereas its lesion enhances persistent inflammatory pain-related behaviour (Sotres-Bayon et al., 2001).The stimulation of the mediodorsal and anteromedial thalamic nuclei enhances self-injury behaviour induced by inflammation (Torres-Lopez et al., 2000). In regard of the anterior cingulate cortex, a diminished response to inflammation after the administration of systemic amantadine is impaired by the microinjection of haloperidol (a dopaminergic antagonist) into this structure (Coffeen et al., 2009). The extracellular signalregulated kinase cascade, which is a key modulator of pain processing, is activated by inflammation in the amygdala (Carrasquillo and Gereau, 2008). Evidence from functional imaging studies also shows the activation of pain matrix-related structures, including the insular cortex, after the induction of inflammatory processes in rats (Shih et al., 2008a,b). The lesion of either or both RAICs diminishes neuropathic painrelated behaviours in the two different models tested in this study. This result is in line with previous evidence obtained from both human and animal studies. Patients with previous nerve injury show functional activation of the insular cortex both with allodynia and hyperalgesia (Hsieh et al., 1995; Witting et al., 2006). Animal studies have also demonstrated the role of the insular cortex after neuropathy. In a model of chronic constriction injury of the trigeminal nerve, there is expression of the extracellular signal-regulated kinase cascade in the dysgranular and agranular insular cortices (Alvarez et al., 2009). Also, the pharmacological manipulation of the dopaminergic system directly in the RAIC modifies neuropathic pain-like behaviour (Coffeen et al., 2008).

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Interestingly, regardless of the side of the RAIC lesion (contralateral, ipsilateral or bilateral), there is a diminished inflammatory and neuropathic pain-like behaviour response. Insular lesions in humans produce a lateralised pain asymbolia (Berthier et al., 1988; Masson et al., 1991). With this in mind we intended to test if this lateralization would be replicated in a controlled animal model. The results in this work suggest that there is no lateralization in pain-like behaviour after RAIC’s lesion in rats. There is recent evidence about lateralization in animals regarding motor performance. However, the evidence regarding lateralization of somatosensory input is contradictory and inconsistent (Tommasi, 2009). Our results oppose those in which a lateralised role of pain matrix structures is found (Bianki and Snarskii, 1988; Carrasquillo and Gereau, 2008). Nevertheless, when both RAICs had a lesion performed there is a tendency towards a more diminished painlike behaviour which is not significant. Acknowledgments This project was partially supported by CONACyT Grant 62433 for FP and INPRF Grant 3230. UC received support from a CONACyT Scholarship 185496. References Afif A, Hoffmann D, Minotti L, Benabid AL, Kahane P. Middle short gyrus of the insula implicated in pain processing. Pain 2008;138:546–55. Alvarez P, Dieb W, Hafidi A, Voisin DL, Dallel R. Insular cortex representation of dynamic mechanical allodynia in trigeminal neuropathic rats. Neurobiol Dis 2009;33:89–95. Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 1996;22:229–44. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87–107. Berthier M, Starkstein S, Leiguarda R. Asymbolia for pain: a sensory-limbic disconnection syndrome. Ann Neurol 1988;24:41–9. Bianki VL, Snarskii SI. The lateralization of hemispheric control over pain-induced vocalizations in rats. Zh Vyssh Nerv Deiat Im I P Pavlova 1988;38:939–44. Bowsher D, Brooks J, Enevoldson P. Central representation of somatic sensations in the parietal operculum (SII) and insula. Eur Neurol 2004;52:211–25. Brooks JC, Nurmikko TJ, Bimson WE, Singh KD, Roberts N. FMRI of thermal pain: effects of stimulus laterality and attention. Neuroimage 2002;15:293–301. Carrasquillo Y, Gereau RW. Hemispheric lateralization of a molecular signal for pain modulation in the amygdala. Mol Pain 2008;4:24. Coderre TJ, Melzack R. Procedures which increase acute pain sensitivity also increase autotomy. Exp Neurol 1986;92:713–22. Coffeen U, Lopez-Avila A, Ortega-Legaspi JM, del Angel R, Lopez-Munoz FJ, Pellicer F. Dopamine receptors in the anterior insular cortex modulate long-term nociception in the rat. Eur J Pain 2008;12:535–43. Coffeen U, Lopez-Avila A, Pellicer F. Systemic amantadine diminishes inflammatory and neuropathic nociception in the rat. Salud Ment 2009;32(2):139–44. Coghill RC, Gilron I, Iadarola MJ. Hemispheric lateralization of somatosensory processing. J Neurophysiol 2001;85:2602–12. Coghill RC, Talbot JD, Evans AC, Meyer E, Gjedde A, Bushnell MC, et al. Distributed processing of pain and vibration by the human brain. J Neurosci 1994;14:4095–108. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994;53:55–63. Endo T, Spenger C, Hao J, Tominaga T, Wiesenfeld-Hallin Z, Olson L, et al. Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury. Pain 2008;138:292–300. Greenspan JD, Lee RR, Lenz FA. Pain sensitivity alterations as a function of lesion location in the parasylvian cortex. Pain 1999;81:273–82. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988;32:77–88. Hess A, Sergejeva M, Budinsky L, Zeilhofer HU, Brune K. Imaging of hyperalgesia in rats by functional MRI. Eur J Pain 2007;11:109–19. Hofbauer RK, Rainville P, Duncan GH, Bushnell MC. Cortical representation of the sensory dimension of pain. J Neurophysiol 2001;86:402–11. Hsieh JC, Belfrage M, Stone-Elander S, Hansson P, Ingvar M. Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain 1995;63:225–36. Hsieh JC, Hannerz J, Ingvar M. Right-lateralised central processing for pain of nitroglycerin-induced cluster headache. Pain 1996;67:59–68. Jasmin L, Burkey AR, Granato A, Ohara PT. Rostral agranular insular cortex and pain areas of the central nervous system: a tract-tracing study in the rat. J Comp Neurol 2004;468:425–40.

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