Spinal cord fractalkine (CX3CL1) signaling is critical for neuronal sensitization in experimental nonspecific, myofascial low back pain

Abstract

Neuroactive substances released by activated microglia contribute to hyperexcitability of spinal dorsal horn neurons in many animal models of chronic pain. An important feedback loop mechanism is via release of fractalkine (CX3CL1) from primary afferent terminals and dorsal horn neurons and binding to CX3CR1 receptors on microglial cells. We studied the involvement of fractalkine signaling in latent and manifest spinal sensitization induced by two injections of nerve growth factor (NGF) into the lumbar multifidus muscle as a model for myofascial low back pain. Single dorsal horn neurons were recorded in vivo to study their receptive fields and spontaneous activity. Under intrathecal vehicle application, the two NGF injections led to an increased proportion of neurons responding to stimulation of deep tissues (41%), to receptive field expansion into the hind limb (15%), and to resting activity (53%). Blocking fractalkine signaling by continuous intrathecal administration of neutralizing antibodies completely prevented these signs of spinal sensitization to a similar extent as in a previous study with the microglia inhibitor minocycline. Reversely, fractalkine itself induced similar sensitization in a dose dependent manner (for 200 ng/ml: 45% deep tissue responses, 24% receptive field expansion, 45% resting activity) as repeated nociceptive stimulation by intramuscular NGF injections. A subsequent single NGF injection did not have an additive effect. Our data suggest that neuron to microglia signaling via the CX3CL1-CX3CR1 pathway is critically involved in the initiation of non-specific, myofascial low back pain through repetitive nociceptive stimuli.

Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury

“…CX3CL1 (also called fractalkine), the only member of the C-X3-C group, is constitutively expressed in the neurons of the normal peripheral nervous system and the central nervous system [ 68 , 69 ]. Chemokine pairs CX3CL1/CX3CR1 are involved in neuropathic pain via neuron-microglia interaction in the spinal cord [ 70 – 72 ]. P38, a member of mitogen-activated protein kinases (MAPKs), is an important downstream kinase of CX3CL1/CX3CR1 signaling [ 73 – 75 ].…”

Fractalkine/CX3CR1 Pathway in Neuropathic Pain: An Update

“…Thermal hyperalgesia and mechanical allodynia can also be elicited in naïve animals by an intrathecal injection of FKN ( 44 ) and both effects are abrogated in CX 3 CR 1 knockout mice ( 34 , 45 ). In addition, the administration of a neutralizing antibody against CX 3 CR 1 ( 46 , 47 ) reduces pain-like behaviours in neuropathic pain models, indicating that microglia-mediated mechanisms contribute to nociceptive hypersensitivity. Injection of FKN, after unique binding to CX 3 CR 1 , activates p38 MAPK signalling pathway ( 34 ).…”

Sex-Related Pain Behavioral Differences following Unilateral NGF Injections in a Rat Model of Low Back Pain

“…The time delay and magnitude of the contralateral sensitivity also aligns well with the process being dependent on an immune-related and/or diffusion process. In male rats, the early stages of pain development, wherein primary afferent priming via NGF exposure leads to spinal neuronal sensitization in this unilateral NGF-LBP model, depend initially on microglial activation and are maintained by astrocyte activation [ 29 , 54 ]. Additional work on the presence, level, and mechanisms of immune cell activation throughout the spinal cord in male and female rodents should be considered [ 7 ].…”