Pruritus is an important physiological sensation mediated by the somatosensory system, and its clinical significance is increasingly recognized. Based on the underlying mechanisms, pruritus can be classified into histaminergic and non-histaminergic types. Non-histaminergic pruritus constitutes the major form of most chronic pruritus conditions and often shows poor response to conventional antihistamines. The gastrin-releasing peptide receptor (GRPR) in the spinal cord, serving as a pruritus-specific receptor, plays a critical role in the transmission of non-histaminergic pruritic signals. The κ-opioid receptor (KOR) and the μ-opioid receptor (MOR) exert opposite effects in pruritus regulation: MOR activation promotes pruritus, whereas KOR activation produces inhibitory effects. This review systematically elaborates on the multiple molecular mechanisms through which KOR inhibits pruritus, with a focus on the direct inhibition of GRPR function via protein kinase Cδ (PKCδ)-mediated phosphorylation, interference with intracellular calcium signaling, potential modulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and comprehensive regulation of pruritic pathways through signaling molecules such as Gβγ and β-arrestin 2. Together, these mechanisms constitute the basis for KOR-mediated regulation of pruritic signals at the spinal level. Although KOR agonists (e.g., TRK-820, CR845) have shown therapeutic potential for chronic pruritus in clinical studies, translational challenges such as species differences and cross-talk among signaling pathways warrant further attention. In-depth elucidation of the KOR regulatory network not only provides novel insights into the physiological and pathological mechanisms of pruritus but also establishes a solid theoretical foundation for the development of novel, highly-targeted anti-pruritus drugs with fewer side effects.