• EA-PC6 reduced acute thermal nociceptive responses and neuropathy-induced mechanical allodynia; these effects were prevented by systemic or intra-vlPAG injection of an antagonist of OX1Rs or CB1Rs, but not by opioid receptor antagonists.• EA-PC6 increased the number of c-Fos-immunoreactive hypothalamic orexin neurons, and led to higher orexin A and lower GABA levels in the vlPAG.• EA-PC6-induced nociception was prevented by intra-vlPAG inhibition of 2-AG synthesis and was attenuated in Cnr1–/– mice. This evidence concerns the gene HCRT and neuropathy.