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.