Attenuation of negative pain affect produced by unilateral spinal nerve injury in the rat following anterior cingulate cortex activation

The affective and the sensory dimensions of pain processing can be differentiated in humans through the use of questionnaires and verbal communication. It is difficult to dissociate these two components of pain processing in rodents, and an understanding of the underlying mechanisms for each component is unclear. The quantification of a novel behavioral response to a repeated noxious cutaneous stimulus together with a measurement of tactile allodynia in nerve-injured rats might be used to differentially explore the sensory and affective components of pain processing in the rat. The present study utilized electrical stimulation of the anterior cingulate cortex, a structure implicated in affective pain processing but not sensory processing, in nerve-injured rats (L5 spinal nerve ligation) and found that the aversive quality of noxious cutaneous hindpaw stimulation was attenuated. There were no effects on sensory processing, because anterior cingulate cortex stimulation did not produce an anti-allodynic effect in L5 spinal nerve ligation animals. Furthermore, anterior cingulate cortex stimulation in animals with bilateral ventrolateral periaqueductal gray area lesions did not affect tactile sensitivity in L5 spinal nerve ligation rats, indicating that an endogenous pain suppression system was not likely activated by anterior cingulate cortex stimulation. However, bilateral ventrolateral periaqueductal gray area lesions in L5 spinal nerve ligation rats blocked the effect produced by anterior cingulate cortex stimulation in the place escape/avoidance paradigm. Specifically, these animals avoided noxious stimulation of the allodynic paw significantly more than anterior cingulate cortex-stimulated, sham or incomplete ventrolateral periaqueductal gray area-lesioned, L5 spinal nerve ligation animals. These findings provide the first quantified report that the activation of the anterior cingulate cortex reduced the aversive quality of repeated noxious tactile stimulation in nerve-injured animals without interfering with normal sensory processing. This effect might require the presence of an intact ventrolateral periaqueductal gray area. It is concluded that the selective manipulation of the anterior cingulate cortex has different effects on pain affect and sensory processing in a rodent model of neuropathic pain.

[1]  M. Fanselow.  Neural organization of the defensive behavior system responsible for fear , 1994, Psychonomic bulletin & review.

[2]  S. Stone-Elander,et al.  Anticipatory coping of pain expressed in the human anterior cingulate cortex: a positron emission tomography study , 1999, Neuroscience Letters.

[3]  M. T. Shipley,et al.  Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? , 1994, Trends in Neurosciences.

[4]  M. Zhuo,et al.  Pavlovian fear memory induced by activation in the anterior cingulate cortex , 2005, Molecular pain.

[5]  M. Gabriel,et al.  Neurobiology of Cingulate Cortex and Limbic Thalamus , 1993 .

[6]  H. Fields,et al.  Endogenous pain control mechanisms: Review and hypothesis , 1978, Annals of neurology.

[7]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[8]  A. Mikami,et al.  During pain-avoidance neurons activated in the macaque anterior cingulate and caudate , 2000, Neuroscience Letters.

[9]  P. Fuchs,et al.  A Behavioral Test Paradigm to Measure the Aversive Quality of Inflammatory and Neuropathic Pain in Rats , 2000, Experimental Neurology.

[10]  P. Wall,et al.  Textbook of pain , 1989 .

[11]  Zhi-qi Zhao,et al.  Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats , 2004, Pain.

[12]  Shan Sun,et al.  NMDA receptors in the anterior cingulate cortex mediate pain-related aversion , 2004, Experimental Neurology.

[13]  D. V. Reynolds,et al.  Surgery in the Rat during Electrical Analgesia Induced by Focal Brain Stimulation , 1969, Science.

[14]  S. Stone-Elander,et al.  Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: a positron emission tomography study , 1996, Pain.

[15]  J. Dostrovsky,et al.  Pain-related neurons in the human cingulate cortex , 1999, Nature Neuroscience.

[16]  M. Bushnell,et al.  Pain affect encoded in human anterior cingulate but not somatosensory cortex. , 1997, Science.

[17]  Jin Mo Chung,et al.  An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat , 1992, PAIN.

[18]  P Baraldi,et al.  Temporal and intensity coding of pain in human cortex. , 1998, Journal of neurophysiology.

[19]  Brent A. Vogt,et al.  Structural Organization of Cingulate Cortex: Areas, Neurons, and Somatodendritic Transmitter Receptors , 1993 .

[20]  M. Bushnell,et al.  Dissociation of sensory and affective dimensions of pain using hypnotic modulation , 1999, Pain.

[21]  Akichika Mikami,et al.  Anterior cingulate activity during pain-avoidance and reward tasks in monkeys , 2001, Neuroscience Research.

[22]  E. Peretz.  The effects of lesions of the anterior cingulate cortex on the behavior of the rat. , 1960, Journal of comparative and physiological psychology.

[23]  R. L. Jackson,et al.  Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain , 2004, Experimental Neurology.

[24]  J. Marshall.  THE SKIN SENSES , 1969 .

[25]  B Conrad,et al.  Region‐specific encoding of sensory and affective components of pain in the human brain: A positron emission tomography correlation analysis , 1999, Annals of neurology.

[26]  M. Zimmermann,et al.  Ethical guidelines for investigations of experimental pain in conscious animals , 1983, Pain.

[27]  H. Fields,et al.  The affective component of pain in rodents: Direct evidence for a contribution of the anterior cingulate cortex , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  E. Spierings,et al.  Endogenous pain control mechanisms , 1979, Annals of neurology.

[29]  R. A. Durinyan,et al.  Cortical projections to the periaqueductal grey in the cat: A retrograde horseradish peroxidase study , 1984, Neuroscience Letters.

[30]  R. Melzack,et al.  Electrical stimulation of the cingulum bundle and surrounding cortical tissue reduces formalin-test pain in the rat , 1996, Brain Research.

[31]  W. Dixon,et al.  Efficient analysis of experimental observations. , 1980, Annual review of pharmacology and toxicology.

[32]  M. Koch,et al.  Lesions of the central gray block conditioned fear as measured with the potentiated startle paradigm , 1996, Behavioural Brain Research.

[33]  B. Vogt,et al.  Contributions of anterior cingulate cortex to behaviour. , 1995, Brain : a journal of neurology.

[34]  Jen-Chuen Hsieh,et al.  Central representation of chronic ongoing neuropathic pain studied by positron emission tomography , 1995, PAIN®.

[35]  E L FOLTZ,et al.  Pain "relief" by frontal cingulumotomy. , 1962, Journal of neurosurgery.

[36]  D. Kimble,et al.  Role of cingulate cortex in shock avoidance behavior of rats. , 1968, Journal of comparative and physiological psychology.

[37]  R. Bolles,et al.  Clinical implications of Bolles & Fanselow's pain/fear model , 1980, Behavioral and Brain Sciences.

[38]  P. Fuchs,et al.  Morphine and gabapentin decrease mechanical hyperalgesia and escape/avoidance behavior in a rat model of neuropathic pain , 2000, Neuroscience Letters.

[39]  S. Verma,et al.  Comorbidities in chronic neuropathic pain. , 2004, Pain medicine.

[40]  Michael W. Miller,et al.  Cortical connections between rat cingulate cortex and visual, motor, and postsubicular cortices , 1983, The Journal of comparative neurology.

[41]  Arun K. Senapati,et al.  Electrical stimulation of the anterior cingulate cortex reduces responses of rat dorsal horn neurons to mechanical stimuli. , 2005, Journal of neurophysiology.

[42]  J. Talairach,et al.  The cingulate gyrus and human behaviour. , 1973, Electroencephalography and clinical neurophysiology.

[43]  The memory storehouse , 1994, Trends in Neurosciences.

[44]  D. Mayer,et al.  Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioral analysis , 1974, Pain.