Bzzzzzz! Splat! Ugh! Anyone who has ever been around a campfire during the summer months is familiar with this progression of noises. Mosquito bites and the resulting welts provide unwelcome souvenirs of time spent outdoors. We all know we shouldn’t scratch. Itch like pain is an aversive stimulus that alerts us to threats to the body. But when the itch becomes too unbearable, we all give in. Scratching is designed to remove irritants from the skin (at least temporarily), but don’t be fooled by this instant gratification! Scratching causes tissue damage that increases the severity of the itch by releasing inflammatory particles.
Despite the parallels between itch and pain, itch research and treatment has lagged behind the pain field. Opioids like morphine have effectively been used for ameliorating pain. However, it’s a well-known side-effect that these drugs can worsen itch. So, what is the connection between itch and pain? How is itch interpreted in the brain? Instantaneous relief from itch (scratching for example) is controlled by fast-acting neurotransmission. Prolonged (and more effective) relief involves neuromodulators. The mystery of how these neuromodulators function in itch sensation has recently been revealed in an exciting study by Kardon et al., 2014 that was published in Neuron.
The research team generated a mouse model for chronic itch that we will refer to as Bhlhb5. This mouse has a deletion of a transcription factor that is important for the development of inhibitory neurons in the spinal dorsal horn. Bhlhb5 mutants do not have the spinal inhibitory interneurons that are necessary for normal itch sensation. Inhibiting these neurons (B5-1) results in a dramatic increase in itch. The normal job of these neurons is to release a kappa opioid called dynorphin.
Interestingly, if you increase the amount of dynorphin in the spinal cord, you specifically can reduce itch but not pain – providing an opposite mechanism to the morphine example we discussed earlier. Furthermore, these B5-1 cells are innervated by afferents that respond specifically to menthol, heat, and cold. These are all methods used to relieve itch in humans. If a mouse lacks these B5-1 neurons, administering menthol fails to rescue the itch behavior in these genetically modified mice. The conclusion from this finding is that B5-1 neurons play a role in inhibiting itch when you add counterstimuli, such as menthol or cold.
One of the other interesting points to come out of this paper is that specific neuromodulators may play different roles depending on the context and the somatosensory input. The kappa and mu opioids discussed earlier in this post have specific and often opposing roles. In the limbic system the mu opiods can cause euphoria while the kappa opiods can cause depression and anxiety. This yin and yang of mu and kappa opioids has now been shown to work in the spinal cord where mu opioids target pain and kappa opioids inhibit itch. This type of research lays the groundwork for making morphine administration to patients more tolerable. Co-administration of a drug like nalpbuphine (a kappa opioid enhancer) with morphine could minimize the miserable itch caused by administering a mu opioid.
Kardon A., Junichi Hachisuka, Lindsey M. Snyder, Darren Cameron, Sinead Savage, Xiaoyun Cai, Sergei Karnup, Christopher R. Fan, Gregory M. Hemenway & Carcha S. Bernard & (2014). Dynorphin Acts as a Neuromodulator to Inhibit Itch in the Dorsal Horn of the Spinal Cord, Neuron, 82 (3) 573-586. DOI: http://dx.doi.org/10.1016/j.neuron.2014.02.046