Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.
eLife digest Despite being unpleasant, pain is critical to survival because it acts as a warning for damage or impending harm. Day-to-day pain like a stubbed toe or a pricked finger is called acute pain. It alerts the body to harm but only lasts a short time and usually goes away on its own. Pain that persists more than three months after the damaged tissue has healed is known as chronic pain, and it is a serious problem that is often difficult to treat. Learning more about the causes of chronic pain is necessary to help develop more effective therapies. Nerve pathways in the spinal cord help process pain and other sensory information from the skin and relay it to the brain. These pathways include sensory fibers that carry pain information from the body to the spinal cord, as well as cells that relay this information to the brain. But not much is known about how the nerves and cells in this region prioritize or refine sensory information before sending it to the brain. Now, Smith et al. have used mice to show that nerve cells in the spinal cord that produce the protein calretinin can act as a pain amplifier, causing it to persist. A technique called optogenetics was used to turn on calretinin nerve cells by exposing them to light. This caused the mice to behave like they were in pain even though they had not been harmed, and the behaviour stopped when they were treated with morphine, a powerful painkiller. Further experiments showed that calretinin nerve cells form a highly interconnected network in the spinal cord. These results show that calretinin nerve cells can ‘jump-start’ the pain pathway within the spinal cord, even when there is no painful stimulation of the skin. Turning on these cells even briefly causes behaviours associated with prolonged pain. By revealing that networks of calretinin nerve cells in the spinal cord act like an in-built pain amplifier, the experiments identify these cells as a potential target for new treatments for chronic pain.