The new Afghan-Indian security pact could inflame Pakistan's proxy war against India and threatens Islamabad's regional ambitions in South Asia as its ties with Kabul and Washington hit rock bottom.
Pakistan has been on the defensive as Afghanistan has cosied up to India. Kabul claims the recent murder of its peace envoy Burhanuddin Rabbani was plotted in Pakistan, and has accused Islamabad of hindering the investigation.
Pakistan has been terse about the burgeoning India-Afghanistan alliance.
"Both are sovereign countries and they have the right to do whatever they want to," Prime Minister Yousuf Raza Gilani said in brief response.
But the alliance undermines Pakistan's policy of courting Afghanistan to offset the regional superpower status of India, with which it has fought three wars since independence in 1947, including two over Kashmir.
Fearful of encirclement by its wealthier neighbour, Pakistan has long focussed on Afghanistan -- arming Islamist warlords against the Soviets in the 1980s, backing the Taliban in the 1990s and hedging its bets in the 2000s.
But the new strategic partnership sealed Tuesday, which will see India take a bigger role in training Afghan security forces after already dishing out more than $2 billion in aid, threatens to isolate Pakistan further.
Right-wing newspaper The Nation said the "very disturbing" pact would "create further misunderstandings" that would help neither Pakistan nor Afghanistan "if he (Karzai) wants his country to progress and prosper".
Pakistani military affairs analyst Ayesha Siddiqa went further.
"This pact will definitely lead to a more intense proxy war between India and Pakistan in Afghanistan, because India will be training the Afghan military and Pakistan does not consider this in its interest," she told AFP.
When US-led forces invaded Afghanistan in October 2001 after the 9/11 attacks, Pakistan formally sided with the United States, but has been long accused of playing a double game with its old warlord and Taliban friends.
Those accusations reached fever pitch after the US embassy in Kabul was subject to a 19-hour siege on September 13 and Rabbani was assassinated on September 20.
Those incidents came after the US killing of al Qaeda leader Osama bin Laden on the doorstep of Pakistan's top military academy in May.
The United States launched a concerted campaign last month, accusing Pakistani intelligence of involvement in the embassy attack and demanding the state cut all ties with the Haqqani network, an Afghan Taliban faction.
And although Prime Minister Gilani declared a "victory" in facing down US pressure on the Haqqanis, officials behind the scenes paint a less rosy picture of relations.
"Every time I think we've hit rock bottom, I find both countries have shovel in their hand and are digging further down trying to find a new bottom," one Pakistani security official told AFP on condition of anonymity.
US options for action are limited. Pakistan, which says nearly half the US war effort in Afghanistan is routed through its territory, stonewalled the Haqqani accusations and last week the pressure began to ease off.
Some say Karzai's visit to India was an opportunity to take up where the United States had left off with its accusations -- and strike a chord in India, which blamed the horrific 2008 Mumbai attacks on Pakistani militants.
Yet despite the distrust, Kabul recognises that there can be no resolution to the 10-year Afghan conflict without at least acquiescence from Islamabad.
Karzai on Wednesday sought to ease Pakistan's discomfort, describing it as Afghanistan's "twin brother" -- although "brother" is also a word he uses for the Taliban -- and India as a "great friend".
Nevertheless, analysts say, the Kabul-Delhi partnership may force Pakistan into reappraising its approach to militancy.
"There has to be less obvious support for insurgents in order to prevent much obvious isolation," said AH Nayyar, physics professor and political analyst at Lahore University of Management Sciences.