Effect of subchronic administration of tachykinin antagonists on response of guinea-pigs to mild and severe stress

The effects of subchronic subcutaneous treatment with tachykinin receptor antagonists over nine days on the repeated mild stress response induced by daily subcutaneous injections and on the severe acute stress induced by morphine withdrawal were investigated in guinea-pigs. The NK1 receptor antagonist, L733,060, 0.25 mg/kg, significantly increased locomotor activity of guinea-pigs compared with animals subjected to repeated injection of the inactive enantiomer, but inhibited Fos-like immunoreactivity (Fos-LI) in the hypothalamus. In animals subjected to the acute severe stress of naltrexone-induced morphine withdrawal, treatment with the NK1 antagonist, L733,060, produced reductions in Fos-LI in the spinal dorsal horn, whereas those treated with the NK3 antagonist, SSR146,977, 0.3 mg/kg, had reduced Fos-LI in the dorsal horn, adrenal medulla, nucleus accumbens, ventral tegmental area and periaqueductal grey. Those animals treated with both NK1 and NK3 antagonists also had reduced Fos-LI in the amygdala and paraventricular nucleus of the thalamus. It was concluded that the NK1 antagonist reduced the hypothalamic response to mild stress but the NK3 antagonist was more effective in reducing the severe stress response to morphine withdrawal. Furthermore, combination of NK1 and NK3 antagonists was more effective than either antagonist in reducing the Fos-LI response to morphine withdrawal.

Research Highlights
► The NK1 receptor antagonist, L733,060, reduced the hypothalamic Fos-like immunoreactivity (Fos-LI) response to mild stress in guinea-pigs and reduced Fos-LI response in the dorsal horn following morphine withdrawal.
► The NK3 antagonist, SSR146,977, reduced rearing behaviour and Fos-LI in mesolimbic regions, dorsal horn and adrenal gland following morphine withdrawal.
► A combination of NK1 and NK3 antagonists was more effective than either antagonist in reducing the Fos-LI response to morphine withdrawal.