Malaysian Journal of Medical Sciences School of Medical Sciences, Universiti Sains Malaysia ISSN: 1394-195X Vol. 13, Num. 2, 2006, pp. 11-18

Malaysian Journal of Medical Sciences, Vol. 13, No. 2, July 2006, pp. 11-18

REVIEW ARTICLE

THE ROLE OF THE THALAMUS IN MODULATING PAIN

Che Badariah Ab Aziz & Asma Hayati Ahmad

Department of Physiology, School of Medical Sciences, Universiti Sains Malaysia 16150 Kubang Kerian, Kelantan, Malaysia
Correspondence : Dr. Che Badariah Ab Aziz MBBS (UM), MSc (Physiology) (USM) PhD (University of Nottingham, UK) Department of Physiology School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia Tel : + 609-766 4907, 766 4835 Fax : +609-765 3370 Email : badariah@kb.usm.my

Submitted-20-02-2004, Accepted-03-12-05

Code Number: mj06017

The thalamus is one of the structures that receives projections from multiple ascending pain pathways. The structure is not merely a relay centre but is involved in processing nociceptive information before transmitting the information to various parts of the cortex. The thalamic nuclei are involved in the sensory discriminative and affective motivational components of pain. Generally each group of nucleus has prominent functions in one component for example ventrobasal complex in sensory discriminative component and intralaminar nuclei in affective-motivational component. The thalamus is also part of a network that projects to the spinal cord dorsal horn and modulates ascending nociceptive information. In the animal models of neuropathic pain, changes in the biochemistry, gene expression, thalamic blood flow and response properties of thalamic neurons have been shown. These studies suggest the important contribution of the thalamus in modulating pain in normal and neuropathic pain condition.

Key words : thalamus, pain, electrophysiology, imaging

The classic pain pathway as was previously understood consists of a three-neuron chain that transmits pain information from the periphery to the cerebral cortex (1). The first order neuron has its cell body in the dorsal root ganglion and two axons, one extending distally to the tissue it innervates while the other extending proximally to the dorsal horn of the spinal cord (2). In the dorsal horn, this axon synapses with the second order neuron which in turn will cross the spinal cord through the anterior white commissure and ascends through the lateral spinothalamic tract to the thalamus. In the thalamus, the second order neuron synapses with the third order neuron, which ascends through the internal capsule and corona radiata to the postcentral gyrus of the cerebral cortex (1). This pathway is organized such that within tracts and nuclei up to the cortex, topological relations are maintained and different parts of the body are represented in an ordered arrangement in the postcentral gyrus. This arrangement is called somatotopy (3).

The pain pathway is now understood to be a dual system at each level and the sensation of pain that arrives in the central nervous system is composed of the sensory discriminative component of pain (first pain), and the affective-motivational component of pain (second pain), which is carried separately (1). In addition, there are also afferents from the spinal cord to pain-mediating areas of the brain stem, local modulating circuits in the spinal cord, and descending pain pathways from the cortex, hypothalamus, and brain stem to the spinal cord that make up the descending facilitation and descending inhibition of pain (4). The spinothalamic pathway that is thought to be concerned with the sensory discriminatory qualities of the stimulus originates primarily from neurons in the neck of the dorsal horn and terminates within the ventroposterior and ventrobasal thalamus, which then project upon the cortex (1). The second pathway (affectivemotivational), which is more extensive, is derived mainly from lamina 1 neurons of the dorsal horn that express the neurokinin 1 (NK1) receptor and terminates within the parabrachial area and periaqueductal grey. These areas in turn project on brain areas such as the hypothalamus and amygdala that modulate the affective dimensions of pain and control autonomic activity.

Integration of sensory discriminative, affective motivational and cognitive-evaluative components contributes to the pain response in an individual (5). The sensory discriminative aspects of pain include quality, location and intensity processing (6) while affective-emotional component of pain comprises the unpleasant character of pain perception (7). The cognitive component is involved in the attention, anticipation and memory of past experiences and this component can interact with the other components giving rise to modulation of pain (8). Studies have been conducted to investigate the involvement of supra-spinal structures in pain modulation (9, 10, 11, 12, 13).

The thalamus is one of the supra-spinal structures that has been extensively investigated as it receives projections from multiple ascending pathways. Spinal lamina I neurons project extensively to the ventrobasal complex (ventral posterolateral + ventral posteromedial) and to the posterior group thalamic nuclei (14, 15, 16). The nociceptive neurons from the ventrobasal complex mainly project to the primary somatosensory cortex and this pathway constitutes the lateral pain system that plays an important role in the discrimination of stimuli (6, 17). The affective-motivational aspect of pain is mediated by the medial pain pathway, which includes the intralaminar thalamic nuclei (18) and posterior aspect of ventromedial thalamic nuclei (19) that project to somatosensory cortex and limbic structures (20). The deeper spinal lamina (V/VI) conveys nociceptive messages to the parabrachial internal lateral nucleus that project mainly to the paracentral nucleus (PC) or other intralaminar nuclei (21, 22). The fibers from PC targeted cortical structures e.g. the lateral orbital, lateral agranular and the dorsomedial prefrontal areas (23) that have an important role in cognitive functions, aggressive behaviour and emotional states (24, 25, 26). Neurons originated from lamina VII/VIII project to the medullary reticular formation (27, 28), ventrolateral periaqueductal (29) and intralaminar thalamic nuclei (30). There is extensive projection from the intralaminar nuclei to the cortex, including to the anterior cingulate cortex, subserving the motivational aspects of pain (31). These brain structures including the thalamus are parts of a neural network that are involved in pain modulation that require further investigations to understand the complexity of pain perception.

The ventral posterolateral (VPL) thalamic nucleus is one of the termination sites for the spinothalamic tract. VPL neurons respond to innocuous and noxious mechanical stimuli and some of the neurons respond to visceral nociception e.g. intraperitoneal injection of bradykinin (32) and uterine distension (33). Electrophysiological studies have reported the excitatory responses of neurons to nociceptive stimulation in (34) other thalamic nuclei including the intralaminar complex (35), nucleus submedius (36), posterior complex (37) and ventromedial thalamus (38). In contrast, nociceptive inputs inhibit a significant proportion of neuronal evoked responses in reticular thalamic nucleus (39) and reticular thalamic (RT) projections to VPL or ventrobasal complex may serve to modulate the ascending information and thus, RT has an important role in processing the sensory information (40).

Studies have shown that VPL nociceptive neurons have restricted receptive fields and precisely encode the intensity of noxious stimuli (32, 41) and these characteristics are consistent with the functions of lateral pain pathway. The nociceptive neurons in other nucleus might have a larger receptive field including the ventromedial nucleus that respond to noxious mechanical and thermal stimulation from any part of the body (42). The ventromedial nociceptive neurons do not respond to innocuous stimuli and these neurons project to widespread areas of the neocortex (42). These fibres might be part of a neural network that is involved in the attentional reactions and/or the coordination of motor responses to pain (19, 42). Another thalamic structure, posterior complex (Po), has a close relationship with the retroinsular cortex and probably has an important role in the motivational affective responses of pain (43). The Po thalamic neurons respond to noxious mechanical stimuli (37) and electrical tooth pulp stimulation (44). It is reported that in cats, some of the neurons have large bilateral receptive field (45) while another report described that of a smaller restrictive field in monkeys (37). The different characteristics of Po neurons might be due to different species used (46) or due to high sensitivity of Po neurons to anaesthetics (47, 48).

There is a large amount of evidence that describe the important contribution of the thalamus to hyperalgesic (increase painful response to noxious stimuli) responses associated with peripheral injury. Studies in rats have shown that following hindpaw inflammation or peripheral nerve injury, ventrobasal (Ventral posterolateral plus ventral posteromedial) thalamic neurons exhibited lowered thresholds and enhanced peripherally-evoked responses (49, 50, 51, 9). At the spinal level, some reports have demonstrated that there were no changes in neural responses following hind paw inflammation (52) and peripheral nerve injury (53, 54) and this suggested that the heightened responses of VPL neurons are not merely due to peripheral sensitization or changes at the spinal level.

Another thalamic nucleus that receives considerable attention is the nucleus submedius (Sm). The Sm has a close relationship with ventrolateral orbital cortex (VLO) and periaqueductal region (55, 56, 57) that forms a part of descending inhibiting system (58, 59). Extracellular recordings demonstrated that the Sm neurons responded to noxious electrical, chemical stimuli (60), mechanical and thermal stimuli (61). A few studies have also reported that the Sm neurons respond to visceral stimulation including colorectal balloon distension (62; 63) and intraperitoneal injection of formalin or hypertonic saline (60). The response to noxious stimuli can be excitatory or inhibitory (60, 61). The excitatory and inhibitory evoked responses could be eliminated or depressed by intravenous administration of morphine and the effects could be reversed with opioid antagonist, naloxone (61). The presence of two types of cells, that is on cells and off cells have been reported in other region e.g. rostral ventromedulla (64, 65) and periaqueductal region (66). Reports have shown that opioid antinociception is mediated by inhibition of on-cells and excitation of off-cells that activate the Sm-VLO-PAG pathway that modulates nociceptive inputs at spinal cord level (61, 67). The modulating role of Sm is supported by studies that show electrical stimulation of Sm leads to inhibition of noxious evoked responses of dorsal horn neurons (68) and depression of tail-flick reflex in rats (69).

Noxious stimulation activates the neural pain pathway and increases the neural activity in certain areas of the brain and the activity can be indicated by increases in the regional cerebral blood flow (CBF) in positron emission tomography (PET) or blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging (fMRI). The changes in the cerebral blood flow are mediated by interaction of sympathetic b-receptors, ATP sensitive potassium channels and the release of nitric oxide (70). Imaging studies have been widely used to investigate the haemodynamic of brain responses to pain in human and animals (10, 11, 12, 71, 72, 73, 74, 75). Investigations on how the brain structures contribute to the overall pain experience are being conducted to improve understanding of nociceptive processing in the central nervous system. The functional imaging investigation is a reliable method to determine the pain response in different brain regions as signal intensity and activated areas are different during noxious and innocuous stimulation (76). Furthermore the signal intensity correlates parametrically with the pain response (77). The thalamus is one of the areas activated as a response to noxious stimulation in normal subjects (78, 79, 80). Application of painful laser stimulation on human subjects produced greater activation in the contralateral primary somatosensory cortex and thalamus (81). Another report has shown the functional association between medial thalamus and the anterior cingulated cortex (ACC). Electrical stimulation of the medial thalamic nuclei produced an increase in the signal in the anterior cingulated cortex (ACC) (20) suggesting involvement of the medial thalamus in affective-motivational component of pain.

Attention is an aspect of cognitive component of pain and it is well known that distraction during painful stimulation reduces the subjective pain sensation in a subject (82, 83, 84). Attention to a noxious stimulus e.g. thermal, activate a large neural network including the prefrontal, posterior parietal, anterior cingulated cortices and thalamus (85). Distraction from the thermal stimuli significantly increased the activation in posterior part of the insular cortex (86), periaqueductal gray (PAG) and posterior thalamus (8). Valet et al (2004) (8) has suggested that the functional interactions between PAG and the posterior thalamus are likely to be involved in the network of pain modulation.

Involvement of the thalamus in processing and modulating nociceptive information in neuropathic pain has been shown in various imaging studies. In unstimulated rats (basal) cerebral blood flow in multiple thalamic nuclei including the VPL, ventral medial and posterior nuclear group, was increased in neuropathic rats compared to sham-operated rats (73) and this finding is consistent with the spontaneous pain related behaviour exhibited by the neuropathic rats. It is also interesting to note the correlation of pain behaviour e.g. mechanical allodynia, that was maximal for two weeks after the nerve injury, matched the changes of blood flow in ventral lateral and VPL, in neuropathic rats (74). Imaging studies conducted in human supported the role of the thalamus in the development of neuropathic pain (71, 72, 75). Reports demonstrate an enhanced activity in the medial pain pathway, including the medial thalamus and anterior insula, with application of an innocuous thermal stimulus in human subjects presenting with heat allodynia (87, 88). The enhanced activity of the medial thalamus was not seen in subjects who have normal heat pain (87, 88). A different study reported a reduction in thalamic signals in patients with chronic neuropathic pain and this might be related to alteration in the thalamic blood flow and neural activity (89). All these observations are different presentations of the thalamus in neuropathic pain condition and are suggestive of supraspinal plasticity involving the thalamus following peripheral injury.

It has been observed from electrophysiological and functional imaging studies that functional changes occur in the thalamus in neuropathic pain condition. The important contribution of the thalamus in neuropathic pain is also supported by other studies including immuno-histochemistry studies. The expression of an early gene, c-fos, is considered as an early marker of long-term functional changes in the neuronal activity. Following noxious stimulation, induction of c-fos expression has been shown in a number of thalamic nuclei e.g. midline nuclei, intralaminar nuclei, paraventricular nucleus and VPL (70, 90, 91). The level of c-fos increased in a few supraspinal regions including the thalamus, frontal cortex and periaqueductal gray four days after sciatic nerve ligation (92). Reorganization of thalamic neurons can be observed within six hours after ligation of sciatic nerve with changes in receptive fields evoked responses to noxious stimuli and the strength of cross-correlation of firing of the thalamic neurons (93). Following peripheral nerve injury, biochemical abnormalities are also reported in the thalamus e.g. reduced serotonin (5-HT) release in the contralateral ventrobasal complex (94) that can reduce the inhibitory input to the spinal cord projections and thalamic relay neurons (95). This will ultimately lead to diminish antinociception or even facilitation of neurons that increases the pain perception.

Studies have shown that NMDA receptors are involved in the somatosensory and nociceptive transmission in the thalamus (95, 96). The NMDA receptors in VPL are important in the development and maintenance of hyperalgesia in the rats (97, 98). Blockade of NMDA receptors in the thalamus reduced nociceptive transmission in neuropathic (98, 99) and normal rats (100). Although NMDA receptor subunits have been found in the medial thalamus (101), its role in mediating nociception in the structure e.g. Sm, has not been proven (102) and requires further investigation.

Studies have suggested that the thalamus is an important structure that mediates different components of pain: sensory discriminative (lateral pain pathway) and affective-motivational (medial pain pathway) components. The thalamus is also involved in the descending inhibition to modulate nociceptive inputs at the dorsal horn of the spinal cord. Changes in the biochemistry, immediate early gene expression, thalamic blood flow and the response properties of thalamic neurons have been demonstrated in neuropathic pain models. These data indicate that the thalamus has an important role to play in the modulation of nociception in normal and neuropathic pain syndrome.

1. Cross SA. Pathophysiology of Pain. Mayo Clin Proc. 1994; 69:375– 83.
2. Woolf CJ. Pain. Neurobiol Dis. 2000; 7: 504-10.
3. Windhorst U. Sensory Systems and Functions: Central Projections of Cutaneous and Enteroceptive Senses. In Greger, R and Windhorst, U eds. Comprehensive Human Physiology. From Cellular Mechanisms to Integration. Vol 1. Berlin: Springer, 1996:623-46.
4. Millan MJ. Descending control of pain. Prog Neurobiol. 2002; 66:355-474.
5. Melzack R. Pain-an overview. Acta Anaesthesiol Scand 1999; 43(9):880-84
6. Andersson JL, Lilja A, Hartvig P, Langstrom B, Gordh T, Handwerker H, et al. Somatotopic organization along the central sulcus, for pain localization in humans, as revealed by positron emission tomography. Exp Brain Res 1997; 117(2): 192-99.
7. Craig AD. A new view of pain as a homeostatic emotion. Trends Neurosci 2003; 26(6) : 303-07.
8. Valet M, Sprenger T, Boecker H, Willoch F, Rummeny E, Conrad B, et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain—an fMRI analysis. Pain 2004; 109(3): 399-408.
9. Abdul Aziz AA, Finn DP, Mason R, Chapman V. Comparison of responses of ventral posterolateral and posterior complex thalamic neurons in naive rats and rats with hindpaw inflammation: mu-opioid receptor mediated inhibitions. Neuropharmacology 2005; 48(4): 607-16.
10. 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(2): 225-36.
11. Lorenz J, Cross D, Minoshima S, Morrow T, Paulson P, Casey K. A unique representation of heat allodynia in the human brain. Neuron 2002; 35(2): 383-93.
12. Porro CA, Lui F, Facchin P, Maieron M, Baraldi P. Percept-related activity in the human somatosensory system: functional magnetic resonance imaging studies. Magn Reson Imaging 2004; 22(10): 1539-548.
13. Zhuo M, Gebhart GF. Characterization of descending inhibition and facilitation from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. Pain 1990; 42(3): 337-50.
14. Apkarian AV, Hodge CJ. Primate spinothalamic pathways: III. Thalamic terminations of the dorsolateral and ventral spinothalamic pathways. J Comp Neurol 1989; 288(3): 493-511.
15. Dado RJ, Katter JT, Giesler GJ, Jr. Spinothalamic and spinohypothalamic tract neurons in the cervical enlargement of rats. I. Locations of antidromically identified axons in the thalamus and hypothalamus. J Neurophysiol 1994; 71(3): 959-80.
16. Katter JT, Dado RJ, Kostarczyk E, Giesler GJ, Jr. Spinothalamic and spinohypothalamic tract neurons in the sacral spinal cord of rats. I. Locations of antidromically identified axons in the cervical cord and diencephalon. J Neurophysiol 1996; 75(6): 2581-605.
17. Kenshalo DR, Jr., Isensee O. Responses of primate SI cortical neurons to noxious stimuli. J Neurophysiol 1983; 50(6): 1479-496.
18. Royce GJ, Mourey RJ. Efferent connections of the centromedian and parafascicular thalamic nuclei: an autoradiographic investigation in the cat. J Comp Neurol 1985; 235(3): 277-300.
19. Desbois C, Villanueva L. The organization of lateral ventromedial thalamic connections in the rat: a link for the distribution of nociceptive signals to widespread cortical regions. Neuroscience 2001; 102(4): 885-98.
20. Shyu BC, Lin CY, Sun JJ, Chen SL, Chang C. BOLD response to direct thalamic stimulation reveals a functional connection between the medial thalamus and the anterior cingulate cortex in the rat. Magn Reson Med 2004; 52(1): 47-55.
21. Bester H, Bourgeais L, Villanueva L, Besson JM, Bernard JF. Differential projections to the intralaminar and gustatory thalamus from the parabrachial area: a PHA-L study in the rat. J Comp Neurol 1999; 405(4): 421-49.
22. Bourgeais L, Monconduit L, Villanueva L, Bernard JF. Parabrachial internal lateral neurons convey nociceptive messages from the deep laminas of the dorsal horn to the intralaminar thalamus. J Neurosci 2001; 21(6): 2159-165.
23. Berendse HW, Groenewegen HJ. Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 1991; 42(1): 73-102.
24. Dalley JW, Cardinal RN, Robbins TW. Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 2004; 28(7): 771-84.
25. Blair RJ. The roles of orbital frontal cortex in the modulation of antisocial behavior. Brain Cogn 2004; 55(1): 198-208.
26. Morgan MA, LeDoux JE. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behav Neurosci 1995; 109(4): 681-88.
27. Chaouch A, Menetrey D, Binder D, Besson JM. Neurons at the origin of the medial component of the bulbopontine spinoreticular tract in the rat: an anatomical study using horseradish peroxidase retrograde transport. J Comp Neurol 1983; 214(3): 309- 20.
28. Menetrey D, Roudier F, Besson JM. Spinal neurons reaching the lateral reticular nucleus as studied in the rat by retrograde transport of horseradish peroxidase. J Comp Neurol 1983; 220(4): 439-52.
29. Vanderhorst VG, Mouton LJ, Blok BF, Holstege G. Distinct cell groups in the lumbosacral cord of the cat project to different areas in the periaqueductal gray. J Comp Neurol 1996; 376(3): 361-85.
30. Carstens E, Trevino DL. Laminar origins of spinothalamic projections in the cat as determined by the retrograde transport of horseradish peroxidase. J Comp Neurol 1978; 182(1): 161-65.
31. Sewards TV, Sewards MA. Representations of motivational drives in mesial cortex, medial thalamus, hypothalamus and midbrain. Brain Res Bull 2003; 61(1): 25-49.
32. Guilbaud G, Peschanski M, Gautron M, Binder D. Neurones responding to noxious stimulation in VB complex and caudal adjacent regions in the thalamus of the rat. Pain 1980; 8(3): 303-18.
33. Berkley KJ, Guilbaud G, Benoist JM, Gautron M. Responses of neurons in and near the thalamic ventrobasal complex of the rat to stimulation of uterus, cervix, vagina, colon, and skin. J Neurophysiol 1993; 69(2): 557-68.
34. Bester H, Bourgeais L, Villanueva L, Besson JM, Bernard JF. Differential projections to the intralaminar and gustatory thalamus from the parabrachial area: a PHA-L study in the rat. J Comp Neurol 1999; 405(4): 421-49.
35. Peschanski M, Guilbaud G, Gautron M. Posterior intralaminar region in rat: neuronal responses to noxious and nonnoxious cutaneous stimuli. Exp Neurol 1981; 72(1): 226-38.
36. Miletic V, Coffield JA. Responses of neurons in the rat nucleus submedius to noxious and innocuous mechanical cutaneous stimulation. Somatosens Mot Res 1989; 6(5-6): 567-87.
37. Apkarian AV, Shi T. Squirrel monkey lateral thalamus. I. Somatic nociresponsive neurons and their relation to spinothalamic terminals.J Neurosci 1994; 14(11 Pt 2): 6779-795.
38. Monconduit L, Bourgeais L, Bernard JF, Villanueva L. Convergence of cutaneous, muscular and visceral noxious inputs onto ventromedial thalamic neurons in the rat. Pain 2003; 103(1-2): 83-91.
39. Yen CT, Shaw FZ. Reticular thalamic responses to nociceptive inputs in anesthetized rats. Brain Res 2003; 968(2): 179-91.
40. Alitto HJ, Usrey WM. Corticothalamic feedback and sensory processing. Curr Opin Neurobiol 2003; 13(4): 440-45.
41. Peschanski M, Guilbaud G, Gautron M, Besson JM. Encoding of noxious heat messages in neurons of the ventrobasal thalamic complex of the rat. Brain Res 1980; 197(2): 401-13.
42. Monconduit L, Bourgeais L, Bernard JF, Le Bars D, Villanueva L. Ventromedial thalamic neurons convey nociceptive signals from the whole body surface to the dorsolateral neocortex. J Neurosci 1999; 19(20): 9063-072.
43. Friedman DP, Murray EA. Thalamic connectivity of the second somatosensory area and neighboring somatosensory fields of the lateral sulcus of the macaque. J Comp Neurol 1986; 252(3): 348-73.
44. Shigenaga Y, Inoki R. Effect of morphine on single unit responses in ventrobasal complex (VB) and posterior nuclear group (PO) following tooth pulp stimulation. Brain Res 1976; 103(1): 152-56.
45. Poggio GF, Mountcastle VB. A study of the functional contributions of the lemniscal and spinothalamic systems to somatic sensibility. Central nervous mechanisms in pain. Bull Johns Hopkins Hosp 1960; 106: 266-316.
46. Craig AD, Dostrovsky JO. Medulla to thalamus. In textbook of pain (ed. Wall PD and Melzack R), pp 183 Churchill-Livingstone, New York.
47. Curry MJ. The exteroceptive properties of neurones in the somatic part of the posterior group (PO). Brain Res 1972; 44(2): 439-62.
48. Nyquist JK, Greenhoot JH. Unit analysis of nonspecific thalamic responses to high-intensity cutaneous input in the cat. Exp Neurol 1974; 42(3): 609-22.
49. Guilbaud G, Kayser V, Benoist JM, Gautron M. Modifications in the responsiveness of rat ventrobasal thalamic neurons at different stages of carrageenin-produced inflammation. Brain Res 1986; 385(1): 86-98.
50. Guilbaud G, Neil A, Benoist JM, Kayser V, Gautron M. Thresholds and encoding of neuronal responses to mechanical stimuli in the ventro-basal thalamus during carrageenin-induced hyperalgesic inflammation in the rat. Exp Brain Res 1987; 68(2): 311-18.
51. Guilbaud G, Benoist JM, Jazat F, Gautron M. Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy. J Neurophysiol 1990; 64(5): 1537- 554.
52. Kelly S, Jhaveri MD, Sagar DR, Kendall DA, Chapman V. Activation of peripheral cannabinoid CB1 receptors inhibits mechanically evoked responses of spinal neurons in noninflamed rats and rats with hindpaw inflammation. Eur J Neurosci 2003; 18(8): 2239-243.
53. Chapman V, Suzuki R, Dickenson AH. Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5-L6. J Physiol 1998; 507 (Pt 3): 881-94.
54. Suzuki R, Chapman V, Dickenson AH. The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain. Pain 1999; 80(1-2): 215-28.
55. Coffield JA, Bowen KK, Miletic V. Retrograde tracing of projections between the nucleus submedius, the ventrolateral orbital cortex, and the midbrain in the rat. J Comp Neurol 1992; 321(3): 488-99.
56. Craig AD, Jr., Wiegand SJ, Price JL. The thalamo-cortical projection of the nucleus submedius in the cat. J Comp Neurol 1982; 206(1): 28-48.
57. Ma W, Peschanski M, Besson JM. The overlap of spinothalamic and dorsal column nuclei projections in the ventrobasal complex of the rat thalamus: a double anterograde labeling study using light microscopy analysis. J Comp Neurol 1986; 245(4): 531-40.
58. Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984; 7: 309-38.
59. Sandkuhler J, Gebhart GF. Relative contributions of the nucleus raphe magnus and adjacent medullary reticular formation to the inhibition by stimulation in the periaqueductal gray of a spinal nociceptive reflex in the pentobarbital-anesthetized rat. Brain Res 1984; 305(1): 77-87.
60. Kawakita K, Dostrovsky JO, Tang JS, Chiang CY. Responses of neurons in the rat thalamic nucleus submedius to cutaneous, muscle and visceral nociceptive stimuli. Pain 1993; 55(3): 327-38.
61. Fu JJ, Tang JS, Yuan B, Jia H. Response of neurons in the thalamic nucleus submedius (Sm) to noxious stimulation and electrophysiological identification of on- and off-cells in rats. Pain 2002; 99(1-2): 243-51.
62. Kawakita K, Sumiya E, Murase K, Okada K. Response characteristics of nucleus submedius neurons to colo-rectal distension in the rat. Neurosci Res 1997; 28(1): 59-66.
63. Yang SW, Follett KA, Piper JG, Ness TJ. The effect of morphine on responses of mediodorsal thalamic nuclei and nucleus submedius neurons to colorectal distension in the rat. Brain Res 1998; 779(1-2): 41-52.
64. Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 1991; 14: 219-45.
65. Heinricher MM, Morgan MM, Fields HL. Direct and indirect actions of morphine on medullary neurons that modulate nociception. Neuroscience 1992;48(3): 533- 43.
66. Heinricher MM, Cheng ZF, Fields HL. Evidence for two classes of nociceptive modulating neurons in the periaqueductal gray. J Neurosci 1987; 7(1): 271-78.
67. Jia H, Xie YF, Xiao DQ, Tang JS. Involvement of GABAergic modulation of the nucleus submedius (Sm) morphine-induced antinociception.Pain 2004; 108(1-2): 28-35.
68. Yang S, Follett KA. Electrical stimulation of thalamic Nucleus Submedius inhibits responses of spinal dorsal horn neurons to colorectal distension in the rat. Brain Res Bull 2003; 59(6): 413-20.
69. Zhang YQ, Tang JS, Yuan B, Jia H. Inhibitory effects of electrical stimulation of thalamic nucleus submedius area on the rat tail flick reflex. Brain Res 1995; 696(1-2) 205-12.
70. Erdos B, Lacza Z, Toth IE, Szelke E, Mersich T, Komjati K, et al. Mechanisms of pain-induced local cerebral blood flow changes in the rat sensory cortex and thalamus. Brain Res 2003; 960(1-2): 219-27.
71. Baron R, Baron Y, Disbrow E, Roberts TP. Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study. Neurology 1999; 53(3): 548-57.
72. Casey KL, Lorenz J, Minoshima S. Insights into the pathophysiology of neuropathic pain through functional brain imaging. Exp Neurol 2003;184 Suppl 1: S80-8.
73. Paulson PE, Morrow TJ, Casey KL. Bilateral behavioral and regional cerebral blood flow changes during painful peripheral mononeuropathy in the rat. Pain 2000; 84(2-3): 233-45.
74. Paulson PE, Casey KL, Morrow TJ. Long-term changes in behavior and regional cerebral blood flow associated with painful peripheral mononeuropathy in the rat. Pain 2002; 95(1-2): 31-40.
75. Witting N, Kupers RC, Svensson P, Arendt-Nielsen L, Gjedde A, Jensen TS. Experimental brush-evoked allodynia activates posterior parietal cortex. Neurology 2001; 57(10): 1817-824.
76. Chang C, Shyu BC. A fMRI study of brain activations during non-noxious and noxious electrical stimulation of the sciatic nerve of rats. Brain Res 2001; 897(1-2): 71-81.
77. Casey KL. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci U S A 1999; 96(14): 7668-674.
78. Casey KL, Minoshima S, Berger KL, Koeppe RA, Morrow TJ, Frey KA. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994; 71(2): 802-07.
79. 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(7): 4095-108.
80. Derbyshire SW, Jones AK. Cerebral responses to a continual tonic pain stimulus measured using positron emission tomography. Pain 1998; 76(1-2): 127-35.
81. Youell PD, Wise RG, Bentley DE, Dickinson MR, King TA, Tracey I, et al. Lateralisation of nociceptive processing in the human brain: a functional magnetic resonance imaging study. Neuroimage 2004; 23(3): 1068-077.
82. Chapman CE, Bushnell MC, Miron D, Duncan GH, Lund JP. Sensory perception during movement in man. Exp Brain Res 1987; 68(3): 516-24.
83. Eccleston C. The attentional control of pain: methodological and theoretical concerns. Pain 1995; 63(1): 3-10.
84. Miron D, Duncan GH, Bushnell MC. Effects of attention on the intensity and unpleasantness of thermal pain. Pain 1989; 39(3): 345-52.
85. Peyron R, Garcia-Larrea L, Gregoire MC, Costes N, Convers P, Lavenne F, et al. Haemodynamic brain responses to acute pain in humans: sensory and attentional networks. Brain 1999; 122 (Pt 9): 1765- 780.
86. Brooks JC, Nurmikko TJ, Bimson WE, Singh KD, Roberts N. fMRI of thermal pain: effects of stimulus laterality and attention. Neuroimage 2002; 15(2): 293- 301.
87. Casey KL, Morrow TJ, Lorenz J, Minoshima S. Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography. J Neurophysiol 2001; 85(2): 951-59.
88. Lorenz J, Casey KL. Imaging of acute versus pathological pain in humans. Eur J Pain 2005; 9(2): 163-65.
89. Iadarola MJ, Max MB, Berman KF, Byas-Smith MG, Coghill RC, Gracely RH, et al. Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain. Pain 1995; 63(1): 55-64.
90. Bullitt E. Induction of c-fos-like protein within the lumbar spinal cord and thalamus of the rat following peripheral stimulation. Brain Res 1989; 493(2): 391- 97.
91. Ceccarelli I, Scaramuzzino A, Massafra C, Aloisi AM. The behavioral and neuronal effects induced by repetitive nociceptive stimulation are affected by gonadal hormones in male rats. Pain 2003; 104(1-2): 35-47.
92. Narita M, Ozaki S, Ise Y, Yajima Y, Suzuki T. Change in the expression of c-fos in the rat brain following sciatic nerve ligation. Neurosci Lett 2003; 352(3): 231- 33.
93. Bruggemann J, Galhardo V, Apkarian AV. Immediate reorganization of the rat somatosensory thalamus after partial ligation of sciatic nerve. J Pain 2001;2(4): 220- 28.
94. Goettl VM, Huang Y, Hackshaw KV, Stephens RL, Jr. Reduced basal release of serotonin from the ventrobasal thalamus of the rat in a model of neuropathic pain. Pain 2002; 99(1-2): 359-66.
95. Salt TE, Eaton SA. Function of non-NMDA receptors and NMDA receptors in synaptic responses to natural somatosensory stimulation in the ventrobasal thalamus. Exp Brain Res 1989; 77(3): 646-52.
96. Dougherty PM, Li YJ, Lenz FA, Rowland L, Mittman S. Evidence that excitatory amino acids mediate afferent input to the primate somatosensory thalamus. Brain Res 1996; 728(2): 267-73.
97. Abarca C, Silva E, Sepulveda MJ, Oliva P, Contreras E. Neurochemical changes after morphine, dizocilpine or riluzole in the ventral posterolateral thalamic nuclei of rats with hyperalgesia. Eur J Pharmacol 2000; 403(1-2): 67-74.
98. Kolhekar R, Murphy S, Gebhart GF. Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat. Pain 1997; 71(1): 31-40.
99. Bordi F, Quartaroli M. Modulation of nociceptive transmission by NMDA/glycine site receptor in the ventroposterolateral nucleus of the thalamus. Pain 2000; 84(2-3): 213-24.
100. Eaton SA, Salt TE. Thalamic NMDA receptors and nociceptive sensory synaptic transmission. Neurosci Lett 1990; 110(3): 297-302.
101. Buller AL, Larson HC, Schneider BE, Beaton JA, Morrisett RA, Monaghan DT. The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition. J Neurosci 1994; 14(9): 5471-484.
102. Xie YF, Tang JS, Jia H. The roles of different types of glutamate receptors involved in the mediation of nucleus submedius (Sm) glutamate-evoked antinociception in the rat. Brain Res 2003; 988(1-2): 146-53.

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