Composition and methods for reducing opioid-induced pruritus
The present invention encompasses methods and combinations for substantially inhibiting the opioid-induced internalization of gastrin-releasing peptide receptor (GRPR) in a pruritus specific neuron. Such methods and combinations provide a direct means of treating opioid-induce pruritus without compromising opioid analgesia.
1. A method for inhibiting opioid-induced internalization of gastrin-releasing peptide receptor (GRPR) in a neuron expressing GRPR in a subject, the method comprising administering to the subject a composition comprising a cell-penetrating peptide fused to the C-terminus of an agent that inhibits the interaction of GRPR with μ opioid receptor 1D (MOR1D), wherein the agent consisting of at least 5 and up to 22 contiguous amino acids of SEQ ID NO: 245 (EHPSTANTVDRTNHQRNEEPSS) wherein the at least 5 contiguous amino acids are selected from the group consisting of SEQ ID NO: 22 (RNEEP), SEQ ID NO: 25 (NEEPS) and SEQ ID NO: 28 (EEPSS), such that the agent inhibits opioid-induced internalization of GRPR by inhibiting the interaction of GRPR with MOR1D, and wherein the cell-penetrating peptide is selected from the group consisting of SEQ ID NO: 549, SEQ ID NO: 550, SEQ ID NO: 551, SEQ ID NO: 552, SEQ ID NO: 553, SEQ ID NO: 554, SEQ ID NO: 555, SEQ ID NO: 556, SEQ ID NO: 557, SEQ ID NO: 558, SEQ ID NO: 559, SEQ ID NO: 560, SEQ ID NO: 561, SEQ ID NO: 562, SEQ ID NO: 563, SEQ ID NO: 564, SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567.
2. A method for inhibiting opioid-induced internalization of gastrin-releasing peptide receptor (GRPR) in a neuron expressing GRPR in a subject, the method comprising administering to the subject a composition comprising a cell-penetrating peptide fused to the C-terminus of an agent that inhibits the interaction of GRPR with μ opioid receptor 1D (MOR1D), wherein the agent is RNEEPSS (SEQ ID NO: 82), such that the agent inhibits opioid-induced internalization of GRPR by inhibiting the interaction of GRPR with MOR1D, and wherein the cell-penetrating peptide is selected from the group consisting of SEQ ID NO: 549, SEQ ID NO: 550, SEQ ID NO: 551, SEQ ID NO: 552, SEQ ID NO: 553, SEQ ID NO: 554, SEQ ID NO: 555, SEQ ID NO: 556, SEQ ID NO: 557, SEQ ID NO: 558, SEQ ID NO: 559, SEQ ID NO: 560, SEQ ID NO: 561, SEQ ID NO: 562, SEQ ID NO: 563, SEQ ID NO: 564, SEQ ID NO: 565, SEQ ID NO: 566 and SEQ ID NO: 567.
3. The method of claim 1 , wherein the cell-penetrating peptide is SEQ ID NO: 550.
4. The method of claim 1 , wherein the composition further comprises at least one analgesic agent.