Ow do we itch?

Trust me, there is a point to the quirky title. I just started my second rotation in Allan Basbaum's lab, whose mantra is 'Pain is in the brain'. The lab studies the neurological basis of pain and its control, with an emphasis on changes in the central circuitry in the spinal cord and the brain. The spinal cord is a fascinating, yet somehow glossed over component of the central nervous system; the few lectures we had on the anatomy of the spinal cord did not do it justice.As my rotation progresses, I am discovering a whole new area of highly complex plastic molecules and circuits and their importance in mediating our ability to detect a range of thermal, mechanical and chemical stimuli and how they are changed in the setting of nerve or tissue injury. More importantly, I am gaining new insight and appreciation of chronic pain as a physiologically and psychologically debilitating condition and the need to elucidate the molecules and cells that are involved in pain processing. 

Before I delve into the actual topic of my post, I just want to give a very brief description of the primary afferents bringing sensory information to the spinal cord (and show off my new found knowledge of neuroanatomy). Firstly, the process by which intense thermal, mechanical or chemical stimuli are detected is called nociception. The population of peripheral nerve fibers that carry this sensory information are appropriately called nociceptors   The cell bodies of nociceptors are located in the trigeminal ganglion for the face and the dorsal root ganglia (DRG) for the body, and have both a peripheral and central axonal branch that innervates their target organ and the spinal cord, respectively. Nociceptors are excited only when stimulus intensities reach a noxious threshold; this suggests that they possess biophysical and molecular properties that enable them to selectively detect and respond to potentially injurious stimuli. There are two major classes of nociceptors. The first includes medium diameter myelinated (Aδ) afferents that mediate acute, well-localized “first” or fast pain. These myelinated afferents differ considerably from the larger diameter and rapidly conducting Aβ fibers that respond to innocuous mechanical stimulation (i.e. light touch). The second class of nociceptor includes small diameter unmyelinated “C” fibers that convey poorly localized, “second” or slow pain. These fibers carry information up to supraspinal structures via distinct pathways; pain is carried by the C fibers and Aδ fibers travel via the spinothalamic tract, while non-painful stimuli are carried by the Aβ fibers  via the dorsal lateral lemniscus. 

A burgeoning interest in the field of pain research is the neuronal basis of itch. That's right, itch; I did a double take too when I found that was my rotation project. Itch was defined more than 340 years ago by the German physician Samuel Hafenreffer as an "unpleasant sensation that elicits the desire or reflex to scratch". The sensation of itch, formally known as pruritus, is most commonly associated with chemical irritants like histamine and a variety of skin diseases. Itch can also result from systemic disorders such as liver and renal dysfunctions. The discovery of neuropathic itch, or itch resulting from nerve damage, spurred investigators to determine specific mediators and neural pathways related to the central processing of itch. These studies have been essential in illustrating the interaction between itch and pain. Think about it, what do we do when we itch? We scratch, sometimes in a manner that causes pain. Animal and human studies have shown that scratch-induced pain can abolish itch, and pain-relieving opioids like morphine generate itch; this hints at an antagonistic interaction. So, what's going on? 

The antagonistic interaction between itch and pain supports the 'specificity theory', which stipulates that  distinct sets of neurons mediate itch and pain. This replaced initial theories on itch that indicated that itch and pain were closely related; weak activation of nociceptors results in itch while strong activation of nociceptors results in pain. This theory, termed as the 'intensity theory' underlined a common central pathway of itch and pain. However, observations that seemingly itch-specific neurons can respond, albeit weakly, to painful stimuli like capsaiscin has prompted researchers to abandon both the 'specificity theory' and 'intensity theory'  in favor of a more plastic 'selectivity theory'. Thus, while there may be distinct set of neurons for pain and itch, more and more studies are suggesting an astonishingly broad overlap between downstream mechanisms of itch and pain signaling. Protease-activated receptor 2 (PAR2) and members of the transient receptor potential (TRP) family have been implicated as targets for both pain and itch receptors, and sensitization of peripheral nerve endings by the protein nerve growth factor (NGF) is a known pathophysiological mechnanism in both chronic itch and pain. Parallels between pain and itch processing are even more evident in the pattern of central sensitization, or the changes that occur in the central nervous system that lead to enhanced responses and/or lower thresholds to a painful or itch-inducing stimulus. fMRI and PET have also identified certain common brain areas like the anterior cingulate cortex and the thalamus that are activated by both pain and itch. 

These similarities and differences in mechanisms of itch and pain sensitization are already being translated into therapeutic approaches to chronic pain and itch. However, as with the studies dealing with chronic pain, it will be important to identify molecules and circuits that are involved in the detection of acute itch in order to treat conditions of chronic itch. That is what I hope to do in my rotation project; aren't you itching to know what I end up finding out? Sorry, I couldn't resist.