What is substance P saporin, and how might it be used to treat chronic pain?
When substance P is released from primary afferent nociceptors, it binds to the neurokinin-1 (NK1) receptor that is located on large numbers of “pain” transmission neurons, many of which are located in lamina I of the superficial dorsal horn. Although antagonists of the NK1 receptors failed in clinical trials, perhaps because selective blockade of the contribution of substance P is insufficient, another approach that targets the NK1 receptor is showing promise. The idea is to ablate the neurons that receive the substance P input. To this end, substance P is conjugated to the plant-derived toxin saporin. When saporin enters cells, it blocks protein synthesis, leading to the death of the cells. By itself saporin cannot enter cells. It requires a carrier, which in this case is substance P. The substance P-saporin conjugate binds to the NK1 receptor, which is then internalized into the neuron, carrying the toxin with it. Intrathecal injection of the conjugate in animals produces a significant reduction of tissue and nerve injury-induced pain (allodynia and hyperalgesia), but it does not interfere significantly with acute pain processing. The molecule is undergoing studies in larger animals with a view to eventual use in patients. This is an irreversible ablative procedure, but it is much more selective compared with, for example, anterolateral cordotomy.