Daniel Johnson rippled the back of the net with just 32 seconds on the clock but an inspired substitution ignited Brentford as they bounced back to win 2-1.
New striker Eoin Doyle marked his first start for PNE by playing a huge part in the opening goal.
Doyle stormed down the left before whipping the ball in towards fellow deadline day signing Stevie May. May pounced and the Bees keeper David Button parried it into the path of an unmarked Johnson who fired home.
Brentford came out fighting in the second half and upped the ante.
But it took the introduction of substitute Sergi Canos to enable Brentford to beat PNE keeper Jordan Pickford who made an unbelievable one handed save in the first half.
Canos beat four North End players within a minute of coming on and teed-up Lasse Vibe who tapped the ball home in the 62nd minute.
Brentford took the lead four minutes later as Jake Bidwell’s header unleashed Marco Djuricin to fire a low powerful shot past Pickford.
The result means PNE slip into the bottom three after picking up six points from their opening eight games.
North End boss Grayson made three changes to the side that played Bristol City on Tuesday.
Chris Humphrey, Bailey Wright and John Welsh all moved to the bench as Doyle, Alan Browne and Marick Vermijl were all handed starts.
PNE made the perfect start as Daniel Johnson opened the scoring in the first minute.
Doyle fizzed the ball into the path of May. The striker’s shot was parried by the keeper into the path of Johnson who smashed the ball home.
May headed over Johnson’s set-piece and his 18-yard strike just looped over the bar as North End hassled Brentford’s defence in the opening 10 minutes.
Brentford player Konstantin Kerschbaumer’s tame shot was saved by Pickford.
Yoann Barbet fouled Garner as he ran towards goal and May stung Button’s palms as he smashed the subsequent set-piece towards goal in the 11th minute.
Pickford pulled off an incredible save to deny Yoann Barbet in the 19th minute. The England U 21 keeper somehow plucked Barbet’s header away from the bottom corner with his left hand. Seconds later Pickford was on hand to stop Marco Djuricin.
Johnson was booked for fouling Josh Clarke and it was Brentford keeper Button’s turn to make a good save as he instinctively tipped Joe Garner’s six-yard header over.
Garner fell over the ball and Josh Clarke robbed it off him but Garner fouls him as he attempted to recover and he picked up his fifth booking so he will miss Tuesday’s match.
Former PNE player Alan McCormack was booked for fouling May seconds later in the 36th minute.
Brentford nearly rippled the back of the net in the 45th minute but Tom Clarke was on hand to block Lasse Vibe’s fierce strike.
And moments just before half-time Djuricin pounced on Browne’s loose pass in North End’s half and teed-up Kerschbaumer who raced past Paul Huntington but Pickford was on hand to thwart him and make another fine save.
Vibe’s curling shot was just deflected wide of Pickford’s left-hand post as Brentford upped the ante at the start of the second half.
Clarke brought down Djuricin just outside the box and Alan Judge rippled the side netting from the subsequent set-piece.
Greg Cunningham pounced on the ball in the Brentford box and unleashed a thunderous strike that just flew over the bar in the 57th minute.
Brentford substitute Sergi Canos made an immediate impact as he beat four players on the right before putting the ball on a plate for Lasse Vibe to tap the ball home from just two yards out in the 62nd minute.
And Brentford took the lead four minutes later as Bidwell flicked the ball into the path of Djuricin who just got ahead of North End’s defence and fired home.
Will Keane came on for Neil Kilkenny in the 72nd and the striker’s first touch was to head Daniel Johnson’s corner way over at the back post.
Substitute Jermaine Udumaga made an impact within seconds of coming on. He looked certain the ripple the back of the net after Canos had teed him up but Clarke managed to get a leg in the way of the goal bound shot in the 78th minute.
Judge sliced the ball wide in the 89th minute but PNE could not get an effort on target in the nine minutes injury time added on.
PNE: Pickford, Vermijl, Clarke, Huntington, Cunningham, Johnson, Kilkenny (Keane, 72), Browne (Brownhill, 84), Doyle, Garner, May (Humphrey, 64). Subs not used: Kirkland, Wright, Woods, Welsh.
Brentford: Button, Bidwell, Dean, Djuricin (Udumaga, 78), McCormack, Kerschbaumer, Judge, Diagouraga, Vibe (O’Connell, 90), Barbet, Clarke (Canos, 61). Subs not used: Bonham, Teber, Woods, Williams, .
Referee: Tim Robinson (West Sussex)