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The present study was undertaken to further investigate the spinal anti-allodynic effects of endomorphins (EMs) and their C-terminal hydrazide modified analogs EM-1-NHNH and EM-2-NHNH in the spared nerve injury (SNI) model of neuropathic pain in mice. Our results demonstrated that intrathecal (i.t.) administration of endomorphin-1 (EM-1), endomorphin-2 (EM-2), EM-1-NHNH and EM-2-NHNH produced potent anti-allodynic effects ipsilaterally in neuropathic pain model. Judging from the area under the curve (AUC) values, these two analogs exhibited higher antinociception than their parent peptides. Moreover, they also displayed significant antinociceptive effects in the contralateral paw administered intrathecally. Interestingly, EM-1 and its analog EM-1-NHNH displayed their antinociception probably by μ-opioid receptor subtype since the μ-opioid receptor antagonist naloxonazine didn't significantly block the anti-allodynia of EM-1 and EM-1-NHNH, which implied a same opioid mechanism. However, the anti-allodynia induced by EM-2, but not EM-2-NHNH was significantly reduced by both μ-opioid antagonist, naloxonazine and κ-antagonist, nor-binaltorphamine (nor-BNI), indicating multiple opioid receptors were involved in the anti-allodynic effects of EM-2. Most importantly, EM-1-NHNH decreased the antinociceptive tolerance, and EM-2-NHNH displayed non-tolerance-forming antinociception. Therefore, C-terminal amide to hydrazide conversion changed the spinal antinociceptive profiles of EMs in neuropathic pain. The present investigation is of great value in the development of novel opioid therapeutics against neuropathic pain.