Aversive effects of the C-fragment of substance P in the dorsal periaqueductal gray matter

There has been an increasing interest in the role of neuropeptides in the integration of brain functions. Besides the well-known positive-reinforcing effects of Substance P (SP) in prosencephalic regions, a role of this neuropeptide in the generation of aversive states in mesencephalic structures has also been envisaged. Evidence from a previous study suggests an involvement of SP in the neural substrates of aversion in the dorsal periaqueductal gray matter (DPAG). Tn the present study, we investigate whether N- and C-terminal fragments of Substance P are responsible for the effects produced by microinjections of SP into the dorsal periaqueductal gray. The results show that SP and its C-terminal fragment SP7-11 produced a behavioral activation with increases in locomotor activity, grooming, and rearings, while the N-terminal fragment S1-7 produced only an increase in vertical exploratory activity. The effects were more pronounced with intermediate doses of SP and its C-fragment, confirming the characteristic bell-shaped dose-effect function of this neuropeptide. The proaversive effects observed with DPAG microinjections of these neuropeptides in the present study gain further relevance when combined with previous reports showing unconditioned and conditioned aversive effects following DPAG microinjections of SP in the place aversion and the elevated plus maze tests, two widely used animal models of anxiety. These results confirm previous data showing that SP has a modulatory role in the DPAG and that its effects are probably due to its C-terminal fragment.