It shouldn't make a difference if the file has been opened or not with Spotlight. Indexing is basically doing that already, and scanning the contents of all your files. The only thing I've heard of people having problems with is iPhoto keywords, but that's easily solved. (create a new keyword and apply it to all your photos, once it's been applied, remove it, and all your existing keywords should work in Spotlight)
I was very impressed with it though. I did a search for . wth my Panther restore dvd in the drive (I had just re-installed the apps off my restore disc) and it brought up about 24,000 results from both it and my hard drive in six seconds. 😱
I did the same with an XP CD, just to see if Apple had maybe stored an index on the disc (I think they have) and it brought up about 30,000 results from the disc and my HDD in about 23 seconds! I think it must have indexed the disc at the same time or something, because after that, no matter what I was searching for, it came up in 2-6 seconds.