Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex

Abstract

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex1, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter γ-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold—producing analgesia or hyperalgesia, respectively—in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABAB-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Cortical injection sites and nociceptive heat paw-withdrawal responses.
Figure 2: Immunocytochemistry of the RAIC, amygdala and brainstem.
Figure 4: Summary of the main findings of the present study.
Figure 3: Nociceptive threshold and Fos immunoreactivity after drug treatment.

References

  1. 1

    Calejesan, A. A., Kim, S. J. & Zhuo, M. Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur. J. Pain 4, 83–96 (2000)

    CAS  Article  Google Scholar 

  2. 2

    Ostrowsky, K. et al. Representation of pain and somatic sensation in the human insula: A study of responses to direct electrical cortical stimulation. Cereb. Cortex 12, 376–385 (2002)

    Article  Google Scholar 

  3. 3

    Berthier, M., Starkstein, S. & Leiguarda, R. Asymbolia for pain: A sensory-limbic disconnection syndrome. Ann. Neurol. 24, 41–49 (1988)

    CAS  Article  Google Scholar 

  4. 4

    Burkey, A. R., Carstens, E. & Jasmin, L. Dopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception. J. Neurosci. 19, 4169–4179 (1999)

    CAS  Article  Google Scholar 

  5. 5

    Greenspan, J. D. & Winfield, J. A. Reversible pain and tactile deficits associated with a cerebral tumor compressing the posterior insula and parietal operculum. Pain 50, 29–39 (1992)

    CAS  Article  Google Scholar 

  6. 6

    Hunt, S. P. & Mantyh, P. W. The molecular dynamics of pain control. Nature Rev. Neurosci. 2, 83–91 (2001)

    CAS  Article  Google Scholar 

  7. 7

    Jung, M. J., Lippert, B., Metcalf, B. W., Bohlen, P. & Schechter, P. J. γ-Vinyl GABA (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T: Effects on brain GABA metabolism in mice. J. Neurochem. 29, 797–802 (1977)

    CAS  Article  Google Scholar 

  8. 8

    New, K. C., Gale, K., Martuza, R. L. & Rabkin, S. D. Novel synthesis and release of GABA in cerebellar granule cell cultures after infection with defective herpes simplex virus vectors expressing glutamic acid decarboxylase. Brain Res. Mol. Brain Res. 61, 121–135 (1998)

    CAS  Article  Google Scholar 

  9. 9

    New, K. C. & Rabkin, S. D. GABA synthesis in astrocytes after infection with defective herpes simplex virus vectors expressing glutamic acid decarboxylase 65 or 67. J. Neurochem. 71, 2304–2312 (1998)

    CAS  Article  Google Scholar 

  10. 10

    Jasmin, L. & Ohara, P. T. Long-term intrathecal catheterization in the rat. J. Neurosci. Methods 110, 81–89 (2001)

    CAS  Article  Google Scholar 

  11. 11

    Proudfit, H. K. & Clark, F. M. The projections of locus coeruleus neurons to the spinal cord. Prog. Brain. Res. 88, 123–141 (1991)

    CAS  Article  Google Scholar 

  12. 12

    Sagen, J. & Proudfit, H. K. Effect of intrathecally administered noradrenergic antagonists on nociception in the rat. Brain Res. 310, 295–301 (1984)

    CAS  Article  Google Scholar 

  13. 13

    Somogyi, J. & Llewellyn-Smith, I. J. Patterns of colocalization of GABA, glutamate and glycine immunoreactivities in terminals that synapse on dendrites of noradrenergic neurons in rat locus coeruleus. Eur. J. Neurosci. 14, 219–228 (2001)

    CAS  Article  Google Scholar 

  14. 14

    Lopantsev, V. & Schwartzkroin, P. A. GABAA-dependent chloride influx modulates GABAB-mediated IPSPs in hippocampal pyramidal cells. J. Neurophysiol. 82, 1218–1223 (1999)

    CAS  Article  Google Scholar 

  15. 15

    Jasmin, L., Boudah, A. & Ohara, P. T. Long-term effects of decreased noradrenergic central nervous system innervation on pain behavior and opioid antinociception. J. Comp. Neurol. 460, 38–55 (2003)

    CAS  Article  Google Scholar 

  16. 16

    Suzuki, R., Morcuende, S., Webber, M., Hunt, S. P. & Dickenson, A. H. Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nature Neurosci. 5, 1319–1326 (2002)

    CAS  Article  Google Scholar 

  17. 17

    Fields, H. L. Pain modulation: expectation, opioid analgesia and virtual pain. Prog. Brain Res. 122, 245–253 (2000)

    CAS  Article  Google Scholar 

  18. 18

    Manning, B. H. A lateralized deficit in morphine antinociception after unilateral inactivation of the central amygdala. J. Neurosci. 18, 9453–9470 (1998)

    CAS  Article  Google Scholar 

  19. 19

    Helmstetter, F. J., Tershner, S. A., Poore, L. H. & Bellgowan, P. S. Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla. Brain Res. 779, 104–118 (1998)

    CAS  Article  Google Scholar 

  20. 20

    Nandigama, P. & Borszcz, G. S. Affective analgesia following the administration of morphine into the amygdala of rats. Brain Res. 959, 343–354 (2003)

    CAS  Article  Google Scholar 

  21. 21

    Watkins, L. R. et al. Neurocircuitry of conditioned inhibition of analgesia: Effects of amygdala, dorsal raphe, ventral medullary, and spinal cord lesions on antianalgesia in the rat. Behav. Neurosci. 112, 360–378 (1998)

    CAS  Article  Google Scholar 

  22. 22

    Killcross, S., Robbins, T. W. & Everitt, B. J. Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala. Nature 388, 377–380 (1997)

    ADS  CAS  Article  Google Scholar 

  23. 23

    LeDoux, J. in The Amygdala (ed. Aggleton, J.) 289–310 (Oxford Univ. Press, 2000)

    Google Scholar 

  24. 24

    Pitkanen, A. in The Amygdala (ed. Aggleton, J.) 31–115 (Oxford Univ. Press, 2000)

    Google Scholar 

  25. 25

    Zhang, S., Tang, J. S., Yuan, B. & Jia, H. Involvement of the frontal ventrolateral orbital cortex in descending inhibition of nociception mediated by the periaqueductal gray in rats. Neurosci. Lett. 224, 142–146 (1997)

    CAS  Article  Google Scholar 

  26. 26

    Everitt, B. J. & Robbins, T. W. in The Amygdala (ed. Aggleton, J.) 401–429 (Wiley-Liss, New York, 1992)

    Google Scholar 

  27. 27

    Brog, J. S., Salyapongse, A., Deutch, A. Y. & Zahm, D. S. The patterns of afferent innervation of the core and shell in the ‘accumbens’ part of the rat ventral striatum: Immunohistochemical detection of retrogradely transported fluoro-gold. J. Comp. Neurol. 338, 255–278 (1993)

    CAS  Article  Google Scholar 

  28. 28

    Berendse, H. W., Galis-de Graaf, Y. & Groenewegen, H. J. Topographical organization and relationship with ventral striatal comparments of prefrontal corticostriatal projections in the rat. J. Comp. Neurol. 316, 314–347 (1992)

    CAS  Article  Google Scholar 

  29. 29

    New, K. C. & Rabkin, S. D. Co-expression of two gene products in the CNS using double-cassette defective herpes simplex virus vectors. Brain Res. Mol. Brain Res. 37, 317–323 (1996)

    CAS  Article  Google Scholar 

  30. 30

    Margeta-Mitrovic, M., Mitrovic, I., Riley, R. C., Jan, L. Y. & Basbaum, A. I. Immunohistochemical localization of GABAB receptors in the rat central nervous system. J. Comp. Neurol. 405, 299–321 (1999)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank J. D. Levine for critical comments, H. J. Ralston for support and encouragement, K. New for constructing the viral vector, U. MacGarvey for assistance with histochemistry, and G. Janni for editorial assistance. This work was funded by NIH (L.J.), NINDS (S.D.R.) and the Koret Foundation (P.T.O.).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Luc Jasmin or Peter T. Ohara.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jasmin, L., Rabkin, S., Granato, A. et al. Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex. Nature 424, 316–320 (2003). https://doi.org/10.1038/nature01808

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing