A shirtless man running in and out of traffic on a Sydney motorway has died after being pepper-sprayed by police during his arrest.

A critical incident investigation is under way into the death of the 41-year-old on Sunday morning.

Officers were called to the M5 at southwestern Moorebank about 3.30am in response to reports from motorists a man was walking in the middle of the motorway.

When they arrived, he was near the Moorebank Avenue off-ramp.

While attempting to take him into custody a struggle ensued, police said.

“He was given directions and was non-responsive to those and a physical altercation occurred (between the man and police),” Assistant Commissioner Stuart Smith said.

Could not be revived

“They ended up on the roadway, where OC spray was deployed without impact.

“Following that, a violent confrontation with the male resulted in him being handcuffed.”

The man lost consciousness at the scene before being treated by paramedics and taken to Liverpool Hospital, but he could not be revived.

An investigation involving a critical incident team from State Crime Command’s Homicide Squad is under way. It will also be subject to independent review.

Police are appealing for anyone on the M5 at the time of the incident and with relevant dashcam vision to contact Liverpool Police or Crime Stoppers.

-AAP