Overall, Johan Santana has enjoyed pitching against the Yankees, but what’s gnawing at him is his last one.

Santana, 4-2 with a 4.59 ERA in eight regular-season starts against the Yankees – including 1-2 with an 8.64 ERA with the Mets- gave up nine runs in three innings in a 15-0 loss last June 14 at the Stadium.

“It motivates me,’’ Santana said. “I don’t go crazy about it, but it’s there. I want to pitch against them again.’’

That game represented a career-high in runs allowed until the Phillies hit him for ten runs, May 2, at Philadelphia. Since then, he’s made three starts with no decisions, but a 2.49 ERA. He gave up two runs in seven innings in his last start, May 18, at Atlanta.

Interleague play has not been kind to Santana since joining the Mets as a free agent from Minnesota, going 2-5 with a 5.11 ERA in seven starts.

Santana will be going against C.C. Sabathia, who, beat him in three of four starts while the latter was with Cleveland.

Here’s tonight’s line-up:

Jose Reyes, SS
Luis Castillo, 2B
Jason Bay, LF
Ike Davis, 1B
David Wright, 3B
Angel Pagan, CF
Rod Barajas, C
Jeff Francoeur, RF
Johan Santana, LP

NOTEBOOK: Daniel Murphy went 5-for-5 with three RBI today for Class A Port St. Lucie. He is expected to join Class AAA Buffalo Tuesday. … Former Mets pitcher Jose Lima, 37, died of a heart attack in Los Angeles. He was 0-4 with the Mets in 2006, his final season in the major leagues. … Reliever Ryota Igarashi was activated from the DL and reliever Manny Acosta was optioned to Buffalo.