What causes listener fatique? cure?

Yes, generally its grain, grittiness, forward high frequencies, as you say. But personally I also find, that anything in your setup, which keeps you from being drawn into the music, so that you are consciously or unconsciously forced to listen to your system instead of the music is eventually very fatiguing.
As far as speakers are concerned, I think we should know your setup and which kind of music you prefer.
Regards

Ohala beat me to it,tubes, in triode, if everything else is good = m&m (music & magic).

Sorry about the user name error Ohlala. Oh,and a 14 hr day of breaking rocks wouldn't help either.Cure for that? A city, state, or fedral job : where you only have to "lean" on the shovel.

my set up: adcom amp, preamp, and cd player from the early 90s (535 amp etc) and definitive tech bp2004 (don't laugh). The system doesn't give me drilling highs, but I can't seem to relax and listen to the music. I am planning to keep the current system for HT and start over for music. I've listened to proac 1.5 and sonus faber gp. I liked them but I want to hear tube stuff first

I find that most metal or inverted dome tweeters cause me listening fatique. Of course, there are exceptions. But, I haven't come across a lot of soft dome tweeters that irritate me. I find that I am becoming increasingly prone to the ill effects of a harsh system(headache, dizzyness, ringing, etc) as time goes by. Not sure if the reason is age, or being around systems that are tube/soft dome tweeter based. The cure is usually available. Either a speaker that features this type of tweeter, or retrofitting your speakers with a good soft dome(have done this). I don't believe that a lower priced speaker has to cause listener fatique. A great example would be the Coincident Triumph. A $1000 speaker featuring the fabulous Vifa D26 silk dome(my FAVORITE cheap tweeter). I have listened to this speaker in a system using an NAD integrated(with the treble set at +6 db), all StraightWire cabling, and budget CD players(Marantz, Pioneer, Sony), and it was still listenable(I didn't say good - but it didn't send me running, which I often do from a bright system) after an extended period.