Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation

Pain. 1999 Mar;80(1-2):127-41. doi: 10.1016/s0304-3959(98)00212-7.


Previous findings indicate that the brain stem descending system becomes more active in modulating spinal nociceptive processes during the development of persistent pain. The present study further identified the supraspinal sites that mediate enhanced descending modulation of behavior hyperalgesia and dorsal horn hyperexcitability (as measured by Fos-like immunoreactivity) produced by subcutaneous complete Freund's adjuvant (CFA). Selective chemical lesions were produced in the nucleus raphe magnus (NRM), the nuclei reticularis gigantocellularis (NGC), or the locus coeruleus/subcoeruleus (LC/SC). Compared to vehicle-injected animals with injection of vehicle alone, microinjection of a serotoninergic neurotoxin 5,7-dihydroxytryptamine into the NRM significantly increased thermal hyperalgesia and Fos protein expression in lumbar spinal cord after hindpaw inflammation. In contrast, the selective bilateral destruction of the NGC with a soma-selective excitotoxic neurotoxin, ibotenic acid, led to an attenuation of hyperalgesia and a reduction of inflammation-induced spinal Fos expression. Furthermore, if the NGC lesion was extended to involve the NRM, the behavioral hyperalgesia and CFA-induced Fos expression were similar to that in vehicle-injected rats. Bilateral LC/SC lesions were produced by microinjections of a noradrenergic neurotoxin, DSP-4. There was a significant increase in inflammation-induced spinal Fos expression, especially in the ipsilateral superficial dorsal horn following LC/SC lesions. These results demonstrated that multiple specific brain stem sites are involved in descending modulation of inflammatory hyperalgesia. Both NRM and LC/SC descending pathways are major sources of enhanced inhibitory modulation in inflamed animals. The persistent hyperalgesia and neuronal hyperexcitability may be mediated in part by a descending pain facilitatory system involving NGC. Thus, the intensity of perceived pain and hyperalgesia is fine-tuned by descending pathways. The imbalance of these modulating systems may be one mechanism underlying variability in acute and chronic pain conditions.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5,6-Dihydroxytryptamine / analogs & derivatives
  • 5,6-Dihydroxytryptamine / toxicity
  • Animals
  • Behavior, Animal
  • Creatinine / analogs & derivatives
  • Creatinine / toxicity
  • Freund's Adjuvant
  • Hindlimb
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology*
  • Ibotenic Acid / toxicity
  • Immunohistochemistry
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / physiopathology*
  • Male
  • Proto-Oncogene Proteins c-fos / biosynthesis*
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / physiopathology*
  • Rats
  • Rats, Sprague-Dawley
  • Reticular Formation / drug effects
  • Reticular Formation / physiopathology*
  • Spinal Cord / metabolism*


  • Proto-Oncogene Proteins c-fos
  • Ibotenic Acid
  • 5,7-dihydroxytryptamine creatinine
  • Freund's Adjuvant
  • Creatinine
  • 5,6-Dihydroxytryptamine