Chronic pain increases brainstem proneurotensin/neuromedin-N mRNA expression: a hybridization-histochemical and immunohistochemical study using three different rat models for chronic nociception.

The role of neurotensin in the central nervous system is poorly understood. Exogenous neurotensin has potent antinociceptive effects when injected into the midbrain periaqueductal gray (PAG). Although it is present in terminals, fibers and perikarya within the PAG and other midbrain regions known for their antinociceptive circuits, it is not known whether endogenous neurotensin modulates nociception. We examined the midbrain in three different rat models for nociception to learn whether acute or chronic pain altered neuronal levels of the proneurotensin/neuromedin N mRNA (neurotensin mRNA). The models were: adjuvant-induced polyarthritis, adjuvant-induced unilateral paw inflammation, and unilateral peripheral mononeuropathy caused by ligation of the sciatic nerve. Behavioral observations confirmed that the expected symptoms developed as previously described. Within each of the three experimental models, we performed in situ hybridization histochemistry on coronal sections from three midbrain levels that included the rostral one-third of the PAG, the middle one-third of the PAG, and the caudal one-third of the PAG. At the level of the rostral PAG, we found that neither chronic nor acute nociception altered the frequencies or distributions of neurons containing neurotensin mRNA. In contrast, at the levels of the mid- and caudal one third of the PAG, the early effects of the nociceptive lesions differed from the chronic effects. During the acute phase of each model, increases in either the frequency or field area of neurons that were hybridization-positive for neurotensin mRNA were confined to the ventromedial PAG and the dorsal raphe nucleus. As the nociceptive stimuli became chronic, the early increases in neurotensin mRNA-containing neurons at the level of the middle third of the ventral PAG were diminished but remained above control levels, while increases in neurotensin mRNA began to occur in the midbrain tegmentum lateral to the PAG. The most striking increases in neurotensin mRNA expression were observed 16-17 days after the onset of nociceptive stimuli. At the level of the mid-PAG and caudal PAG, increased hybridization signal intensities and neuron frequencies occurred within the nucleus cuneiformis and the lateral tegmental nuclei, including the pedunculopontine and microcellular tegmental nuclei, as well as the deep mesencephalic nuclei. Hybridization-positive neurons in the tegmental nuclei were not observed at early stages of lesion development, but were a consistent feature of caudal midbrains after nociception became chronic.(ABSTRACT TRUNCATED AT 400 WORDS)