What is Central Sensitization?

In the previous post on allodynia and hyperalgesia, I mentioned that sensitization of nociceptive neurons in the dorsal horn of the spinal cord were crucial for the development of allodynia and likely contribute strongly to hyperalgesia. When pain scientist and clinicians talk about this type of sensitization they often refer to it as “central sensitization”. What, exactly does this mean?

Central sensitization is loosely defined as an increased response to stimulation that is mediated by amplification of signaling in the central nervous system (CNS). While the stimulation does not necessarily need to be of noxious intensity, for central sensitization to be present it should recruit mechanisms that would signal a noxious response. An example of this is the case of allodynia. Under normal conditions a non-noxious stimuli may not recruit electrophysiological activity in nociceptive neurons in the dorsal horn. On the other hand, following an injury, this same innocuous stimulation may recruit activity in these same central neurons. This would be an example of central sensitization and, in this case, the sensitization would provide a mechanism for allodynia. Central sensitization was first described by Clifford Woolf. In a Nature paper in 1983 he showed that a thermal injury in the periphery caused an amplification of painful stimuli evoked activity coupled to an augmentation of the flexion reflex response (recorded by EMG). Because this reflex is mediated by a dorsal horn – ventral horn reflex arc this gave evidence that amplification of pain signaling was occurring in the CNS. Importantly, he also noted that the injury (to only one paw) stimulated an increase in the reflex arc on the contralateral side of the body. Because this occurred on the side opposite the injury, it could not have been mediated by peripheral mechanisms and must have involved amplification of signaling in the CNS. He termed this phenomena “central sensitization” and realized that such mechanisms could give rise to pain amplification similar to what is seen in humans following an injury or in chronic pain conditions.

In the decades that have followed central sensitization has become an important area of research for pain scientists and a route for therapeutic intervention for pain clinicians. Let’s begin with advances in research:

While the body of literature on this topic is too large to cover in full, there have been several major advances that are worth noting. A major theme that has emerged in research on central sensitization is that this phenomena shares cellular mechanisms with learning and memory. For instance, central sensitization occurs in part because of increased activity in glutamate receptors, including increased NMDA and AMPA receptor activity and a crucial role for group I mGluRs (mGluR1/5). Many of the kinases (these are proteins that phosphorylate proteins) that are involved in learning and memory (like CaMKII alpha and ERK) also play a key role in central sensitization. In addition to these molecular targets, neurons that signal central sensitization have also been identified. These neurons are found in lamina I of the spinal cord and they express the substance P (substance P is a neuropeptide released by nociceptive primary afferent neurons) receptor NK-1. Steve Hunt and Pat Mantyh demonstrated this by ablating these neurons with substance P conjugated to saporin (a cellular toxin). Spinal administration of substance P-saporin ablates experimental hyperalgesia in pre-clinical models showing that these neurons are crucial for the full expression of central sensitization.

Work from the group of Jurgen Sandkuhler has demonstrated that the neurophysiological basis for central sensitization involves, in many cases, a specific form of neuronal plasticity called long-term potentiation (LTP). This LTP is similar to that observed in the hippocampus and other CNS regions except that in a subset of neurons this LTP can be evoked by low frequency stimulation (generally LTP is evoked only by high frequency stimulation). This finding was crucial because in conditions of inflammation or nerve injury nociceptors fire continuously but they do so at a relatively low frequency. Hence, these findings tied activity in nociceptors after an injury to a specific type of neuronal plasticity in a specific subset of spinal cord neurons (that are in lamina I and express the substance P receptor NK-1). These findings are summarized in an OA review written by Sandkuhler.

While I have focused thus far on central sensitization as manifest in the dorsal horn of the spinal cord, it is also important to note that central sensitization can occur in other CNS regions as well. For instance, recent work from the labs of Volker Neugebauer and Rob Gereau have shown that the amygdala is critical for the sensitization of nociceptive responses following nerve injury. Moreover, Mary Heinricher’s group has shown that a region of the brainstem, called the rostral ventromedial medulla (RVM), shows plasticity in its responses to painful stimuli after peripheral injury. Because this brain region sends descending fibers into the spinal cord that amplify nociceptive circuits, it is considered the to be involved in descending pain modulation. The RVM is a major target for cannabinoid and opioid analgesics and it is likely that these classes of compounds inhibit pain by attenuating central sensitization-like responses in these neurons.

Mechanisms of central sensitization have become major targets for pain therapeutics. Basic science research has led to the development of targets that are specifically designed to block or attenuate central sensitization. Some examples are NK1 antagonists (which performed poorly in clinical trials, unfortunately), NMDA receptor antagonists and kinase inhibitors (like ERK inhibitors) which are under investigation as novel analgesics. The clinical rationale for preemptive analgesia (in surgical situations) has its basis in the science of central sensitization. The idea here is that the administration of analgesics prior to surgical intervention can block the development of central sensitization that can occur from nociceptor activation during surgery. This approach has been shown to be effective in many clinical trials.

Since its first description, central sensitization has become a unifying theme for pain research and clinical development. We now know that central sensitization underlies many pain conditions ranging from nerve injury induced allodynia to headache. As we continue to gain a fuller understanding of mechanisms that lead to central sensitization it is likely that new avenues for therapeutic intervention will be developed for the treatment of chronic pain that involve blockade or reversal of central sensitization.