Neuroimmunology of pain is a relatively new field of research that investigates the cross-talk between neurons and components of the immune system in the generation of pain. Neuropathic pain occurs after peripheral or central nerve damage and is thought to be caused by an amplification of nociceptor sensory signals causing pain sensitisation, or “hyperalgesia”.1 Nociceptors are receptors that are activated by a potentially noxious stimulus. These receptors then send a signal to the brain or spinal cord to be interpreted as pain. Non-neuronal receptors including the immune Toll-like receptors (TLRs) have been shown to be implicated in the amplification of pain.2 Ten human TLRs, TLR1 to TLR10 have been discovered, and their primary role is to alert the immune system in response to exogenous pathogens and endogenous cellular contents released during cell death. TLR activation causes pro-inflammatory cytokine release which is useful in clearing an infection, however, activation of TLRs in response to nerve damage, can activate and maintain the nociceptive pathway.2 Current research shows that spinal microglia are a key component in the development and maintenance of neuropathic pain, with an important role for Toll-like receptor 4 (TLR4) as the initiator of hyperalgesia.3

Although the mechanism of neuroimmune induced nociception is yet to be fully determined, microglia are known to be a main cell type causing pain sensitisation which predominantly expresses TLR4.4 Upon peripheral or central nerve damage, spinal microglia are known to be strongly activated.5 It has been shown that following a L5 spinal transection, microglial TLR4 is upregulated.3 Danger-associated molecular patterns (DAMPs), such as saturated fatty acids released following nerve damage, activate TLR4.6 TLR4 triggers a signal cascade that leads to the production of pro- inflammatory cytokines, including IL-1β and TNF. These cytokines indirectly enhance nociceptive signalling via synaptic plasticity in the central terminus.7 Thus, targeting TLR4 may be a future target for pain management. This concept has been supported by a study in which intrathecal TLR4 antisense oligonucleotides were shown to reduce hyperalgesia behaviors in rats and decrease the activation of microglia and pro-inflammatory cytokines.3

It is estimated that 7%-8% of the general population in Europe are living with neuropathic pain.8 Interestingly however, this percentage rises within the subpopulation of patients receiving chemotherapy. Approximately 30% of these patients experience chemotherapeutic-induced peripheral neuropathy even after completion of chemotherapy for 6 months or more.9 Paclitaxel is a common chemotherapeutic used in cancers such as ovarian and breast, and acts by inhibiting the depolymerisation of microtubules to enhance cancer cell death. However, paclitaxel is also known to cause peripheral nerve damage by disrupting axonal transport, in addition to causing spinal microglial activation leading to pain sensitisation.10 I believe that to advance the field, research should focus on developing a TLR4 antagonist drug for the treatment of paclitaxel-induced peripheral neuropathy. The importance of this research is three-fold. Firstly, it will demonstrate the power of controlling immune activation for neurological pain management. This concept was eloquently demonstrated in an animal study where rats with a sciatic chronic constriction injury (CCI) were administered lentivirus containing TLR4 small interfering (si)RNA experienced reduced pain and showed a reduction in pro-inflammatory cytokines TNF-α and IL-1β.11 Secondly, it will reduce the dependence on opioids for pain management. Opioids should be used sparingly for chronic pain in clinical practice not only due to their addictive nature that has become a global epidemic, but also due to the development of opioid analgesic tolerance and opioid induced hyperalgesia.12 The mechanism of opioid induced hyperalgesia is thought to involve activation of μ opioid receptors on microglia.12 Lastly, this treatment has the potential to have immense clinical benefits, as control of pain symptoms have a positive impact on physical and social functioning, sleep, mood, and overall well-being.13

A specific focus on antagonising the effects of TLR4 is important since TLR4 and other adaptor proteins such as TRIF and MyD88 are upregulated in paclitaxel-induced peripheral neuropathy.10 I believe that there should be a focus on the development of an intrathecal TLR4 antagonist. The intrathecal route of administration would minimise systemic immunosuppression, as TLR4 is found in many immune cells throughout the body. Since TLR4 is a membrane-bound receptor, there would not be the extra burden of requiring the drug to be endocytosed by microglia. Interestingly, TLR4 antagonists such as naloxone and naltrexone reverse neuropathic pain in animal models.14 Thus, it is reasonable to infer that this type of TLR4 antagonist treatment may be effective after a select number of doses are administered.1 4

While it was once thought that the nervous system and immune system acted independently, increasing evidence of their interaction has shown that glial cells serve as the connection between both systems.15 This is an exciting area of research as it may provide another route of targeting pain produced by the nervous system via controlling immune system activation. With the promising results of diminished hyperalgesia in animal models via TLR4 inhibition, I believe that a TLR4 antagonist may be a good approach in treating immune mediated pain sensitisation which may also benefit patients with paclitaxel-induced peripheral neuropathy.

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