Non-cytotoxic protein conjugates

A non-cytotoxic protein conjugate for inhibition or reduction of exocytic fusion in a nociceptive sensory afferent cell, comprising:

• (i) a Targeting Moiety (TM), wherein said TM is a nociceptin peptide that binds to a receptor present on said nociceptive sensory afferent cell, wherein said receptor undergoes endocytosis to be incorporated into an endosome within the nociceptive sensory afferent cell, wherein the receptor is an opioid receptor-like 1 (ORL1) receptor, and wherein the TM is SEQ ID NO:6 or 8;
• (ii) a non-cytotoxic protease or a fragment thereof, wherein the protease or protease fragment is a clostridial protease or a neisserial IgA protease or a fragment thereof, and wherein the protease or protease fragment cleaves a protein of the exocytic fusion apparatus of said nociceptive sensory afferent cell;
• and
• (iii) a Translocation Domain, wherein the Translocation Domain translocates the protease or protease fragment from within the endosome, across the endosomal membrane, and into the cytosol of the nociceptive sensory afferent cell, and wherein the Translocation Domain is a translocation domain of a clostridial neurotoxin or from a bacterial or viral source.