Lesion and electrical stimulation of the ventral tegmental area modify persistent nociceptive behavior in the rat

The ventral tegmental area (VTA) has been traditionally related with the control of motor responses. However, some studies show that this area is also involved in the processing of nociceptive information. It has been reported that this nucleus participates in the dissociative analgesia phenomenon. In the few works where electrical stimulation and lesion of the VTA have been performed, evaluated with persistent or chronic pain related behaviors, contradictory results have been obtained. Thus, a more detailed analysis of the role of the VTA in persistent pain is needed. Two series of experiments were performed: lesions of this nucleus were done with radiofrequency, (bilaterally at two points per side using a temperature range from 50 to 80 degrees C), and the VTA was electrically stimulated (10 min daily over 5 days, 2 ms rectangular pulses at 100 Hz during 1 s every 5 s) using two different schemes:10 min before the induction of the nociceptive stimulus and 90 min after the induction of the nociceptive stimulus. The latter allowed us to distinguish if the VTA electrical stimulation had a distinctive antinociceptive effect when applied before or after the induction of the nociceptive stimulus on a persistent pain related behavioral response in the rat, the self injury behavior (SIB). Our results showed that VTA lesions enhanced the occurrence of SIB; while activation of this same nucleus by electrical stimulation after the nociceptive stimulus, but not before, facilitates the analgesic process, expressed as a 1 day delay in SIB onset. These results indicate that the VTA is a brain structure that plays a key role in the processing and modulation of persistent pain information. Data are discussed in terms of the relationship of the VTA with the affective component of pain.

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

[2]  Ronald Melzack,et al.  Analgesia produced by injection of lidocaine into the anterior cingulum bundle of the rat , 1989, Pain.

[3]  J. Stewart,et al.  Opioid receptors in the ventral tegmental area contribute to stress-induced analgesia in the formalin test for tonic pain , 1996, Brain Research.

[4]  M. Levitt Dysesthesias and self-mutilation in humans and subhumans: A review of clinical and experimental studies , 1985, Brain Research Reviews.

[5]  D. Albe-Fessard,et al.  Self-stimulation in the ventral tegmental area suppresses self-mutilation in rats with forelimb deafferentiation , 1984, Neuroscience Letters.

[6]  B. Vogt,et al.  Pain Processing in Four Regions of Human Cingulate Cortex Localized with Co‐registered PET and MR Imaging , 1996, The European journal of neuroscience.

[7]  J. Glowinski,et al.  Differential effects of ascending neurons containing dopamine and noradrenaline in the control of spontaneous activity and of evoked responses in the rat prefrontal cortex , 1988, Neuroscience.

[8]  R. Melzack,et al.  The role of the cingulum bundle in self-mutilation following peripheral neurectomy in the rat , 1991, Experimental Neurology.

[9]  A. López‐Avila,et al.  Electric stimulation of the cingulum bundle precipitates onset of autotomy induced by inflammation in rat , 1999, European journal of pain.

[10]  Patrick D. Wall,et al.  Challenge Of Pain , 1983 .

[11]  R. Godbout,et al.  Inhibitory influence of the mesocortical dopaminergic neurons on their target cells: electrophysiological and pharmacological characterization. , 1991, The Journal of pharmacology and experimental therapeutics.

[12]  J. Fuster The Prefrontal Cortex , 1997 .

[13]  J. Glowinski,et al.  Mediodorsal thalamic evoked responses in the rat prefrontal cortex: influence of the mesocortical DA system. , 1996, Neuroreport.

[14]  J. Glowinski,et al.  Selective activation of the mesocortical DA system by stress , 1976, Nature.

[15]  B. Vogt,et al.  Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex , 1998, Experimental Brain Research.

[16]  M. Zhuo,et al.  Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex , 2000, European journal of pain.

[17]  R. Lane,et al.  Neural Correlates of Levels of Emotional Awareness: Evidence of an Interaction between Emotion and Attention in the Anterior Cingulate Cortex , 1998, Journal of Cognitive Neuroscience.

[18]  J. Stewart,et al.  Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine. , 1998, The Journal of pharmacology and experimental therapeutics.

[19]  G. Guilbaud,et al.  Influence of Timing of Administration on the Analgesic Effect of Bupivacaine Infiltration in Carrageenin-injected Rats , 1996, Anesthesiology.

[20]  Radiofrequency cingulotomy for intractable cancer pain using stereotaxis guided by magnetic resonance imaging. , 1990 .

[21]  J. Han,et al.  Electroacupuncture accelerated the expression of c-Fos protooncogene in dopaminergic neurons in the ventral tegmental area of the rat. , 1993, The International journal of neuroscience.

[22]  R. Melzack,et al.  Analgesia produced by stimulation of limbic structures and its relation to epileptiform after-discharges , 1978, Experimental Neurology.

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

[24]  T. Jay,et al.  Inhibition of hippocampo-prefrontal cortex excitatory responses by the mesocortical DA system , 1995, Neuroreport.

[25]  M. Le Moal,et al.  Mesocorticolimbic dopaminergic network: functional and regulatory roles. , 1991, Physiological reviews.

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

[27]  Alan C. Evans,et al.  Functional imaging of an illusion of pain , 1996, Nature.

[28]  Josef K. Wang Advances in Pain Research and Therapy , 1980 .

[29]  K. Franklin Analgesia and the neural substrate of reward , 1989, Neuroscience & Biobehavioral Reviews.

[30]  S. Jabbur,et al.  Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons , 1997, Brain Research.

[31]  K. Franklin,et al.  6-Hydroxydopamine lesions of the ventral tegmentum abolishd-amphetamine and morphine analgesia in the formalin test but not in the tail flick test , 1990, Brain Research.

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

[33]  J. Glowinski,et al.  Effect of noxious tail pinch on the discharge rate of mesocortical and mesolimbic dopamine neurons: selective activation of the mesocortical system , 1989, Brain Research.

[34]  E. Chudler,et al.  The role of the basal ganglia in nociception and pain , 1995, Pain.

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

[36]  M. Lombard,et al.  The possible participation of a dopaminergic system in mutilating behavior in rats with forelimb deafferentation , 1984, Neuroscience Letters.

[37]  R. Oades,et al.  Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity , 1987, Brain Research Reviews.

[38]  Donald D. Price,et al.  Central nervous system mechanisms of analgesia , 1976, Pain.