The study investigates the role of endogenous cannabinoids, such as anandamide and palmitoylethanolamide (PEA), in the control of pain initiation. Anandamide and PEA were found to attenuate pain behavior produced by chemical damage to cutaneous tissue by interacting with CB1-like and CB2-like cannabinoid receptors, respectively, located outside the central nervous system (CNS). The analgesic effects of anandamide were blocked by the CB1 antagonist SR141716A, while those of PEA were blocked by the CB2 antagonist SR144528. Local injections of anandamide and PEA were more effective than systemic administration, suggesting a peripheral site of action. The synergistic effects of anandamide and PEA in inhibiting formalin-evoked nociception indicate that they may work together to modulate pain initiation. The study also suggests that selective agonists for CB2-like receptors or peripherally administered CB1-like/CB2-like agonists could be potential analgesics without the side effects of centrally acting cannabinimetic or opiate drugs.The study investigates the role of endogenous cannabinoids, such as anandamide and palmitoylethanolamide (PEA), in the control of pain initiation. Anandamide and PEA were found to attenuate pain behavior produced by chemical damage to cutaneous tissue by interacting with CB1-like and CB2-like cannabinoid receptors, respectively, located outside the central nervous system (CNS). The analgesic effects of anandamide were blocked by the CB1 antagonist SR141716A, while those of PEA were blocked by the CB2 antagonist SR144528. Local injections of anandamide and PEA were more effective than systemic administration, suggesting a peripheral site of action. The synergistic effects of anandamide and PEA in inhibiting formalin-evoked nociception indicate that they may work together to modulate pain initiation. The study also suggests that selective agonists for CB2-like receptors or peripherally administered CB1-like/CB2-like agonists could be potential analgesics without the side effects of centrally acting cannabinimetic or opiate drugs.