For me, it was mostly a matter of training my leg muscles to do completely different things. Running is very easy leg motions (picking up and swinging a completely free leg forward, then doing a hard push of short duration. By contrast, biking at its best is a very smooth, continuous motion with no sudden anything required. Biking not only trains the muscles to operate differently, it also builds a lot of muscle mass that isn't even part of the runner's motion. Gone were my long, lean legs of my X-county days!
In my brief racing life, I ran starting mid-fall for a change of pace. I'd run X-country in high school and ran for fun in college so this wasn't new. But that first 8 mile run in October! Wow! did that hurt! I'd build to around 12 and start becoming comfortable, then snows hit and my activities became hit or miss for a while then it was time to start putting on fix gear miles of LSD.