Treating Skeletal Pain: Limitations of Conventional Anti-inflammatory Drugs, and Anti-neurotrophic Factor as a Possible Alternative

Cory J. Xian; Xin-Fu Zhou

Disclosures

Nat Clin Pract Rheumatol. 2009;5(2):92-98. 

In This Article

Neurotrophic Factors in Injury-induced or Inflammatory Pain

Neurotrophins are a family of proteins that are essential for the proliferation, differentiation and survival of primary sensory neurons[30] and, as shown in recent studies, participate in the development of pain states. Each neurotrophin binds with high affinity to a specific receptor tyrosine kinase (Trk), and all bind to the common receptor p75. In adult animals, approximately 40–50% of primary sensory neurons express the nerve growth factor (NGF) receptor TrkA, 20–30% express the brain-derived neurotrophic factor (BDNF) receptor TrkB, and 20–30% of neurons express the neurotrophin 3 (NT3) receptor TrkC. Neurotrophins are expressed in sensory target organs and tissues, such as skin, blood vessels and visceral tissues;[31] BDNF is also highly expressed by a subpopulation of sensory neurons.[32] Neurotrophins released from their targets act on and maintain normal functioning of sensory neurons. In pathological conditions, such as trauma and inflammation, neurotrophins are upregulated by injured tissues,[33] and sensory nerve terminals are activated by target-derived neurotrophins, which participate in tissue healing and the development of pain.

Neurotrophins in Wound and Tissue Repair and Fracture Healing

Apart from its known biological effects on neuronal cells, NGF might also be an important component of the wound healing and tissue repair process. Early studies reported a therapeutic role for NGF in tissue repair, particularly in otherwise untreatable ulcers in patients with diabetes and in patients with severe pressure ulcers.[34] In addition, NGF accelerated the rate of wound healing both in normal mice and in healing-impaired diabetic mice.[35] Interestingly, NGF administered after injury was associated with the promotion of wound healing and increased numbers of fibroblasts and blood capillaries in granulation tissues in mice.[36]

While NGF can be detected in periosteal osteoprogenitor cells in intact bone, NGF protein has also been detected in osteoprogenitor cells, marrow stromal cells, osteoblasts, some chondrocytes, endothelial cells, the periosteal matrix of the fracture callus, and skeletal muscle, suggesting that NGF and all these entities participate in fracture repair and re-innervation.[37] In a mouse model of fractured ribs, immunoreactivity of NGF, BDNF and NT3, and the receptors TrkA and TrkC, was observed in osteoblasts and/or hypertrophic chondrocytes in the bone forming area at the fracture callus.[38] In addition, mRNA levels of these neurotrophins were elevated during the healing process. Localized, intense ingrowth of new sensory nerve fibers containing the neuropeptide CGRP (calcitonin gene-related peptide) was also observed at the fracture callus in rats.[39] As CGRP immunoreactivity coincides with the amount of new bone formation, this finding suggests an association between CGRP-positive innervation and fracture healing.

These findings indicate that neurotrophins might be involved in bone or nerve healing as autocrine and/or paracrine factors during fracture repair. Although treatment with anti-NGF antibodies did not seem to interfere with the bone healing process, as assessed by mechanical testing and histomorphometric analysis,[40] the potential role of neurotrophins and their mechanisms of action in bone fracture healing require further investigation.

Neurotrophins in Injury-induced or Inflammatory Pain

Various studies have shown that neurotrophins, mainly NGF, are involved in the pathophysiology of injury-induced pain in nerve tissues, peripheral tissues and intervertebral discs. Neurotrophins have an established role in neural survival, collateral sprouting of sensory axons,[41,42] and regulation of nociceptive sensory neurons.[43] Increased expression and secretion of NGF, NT3 and BDNF have been implicated in injury-induced neuropathic pain after axotomy of the sensory system or the motor nerve.[44] Interestingly, tibial fracture in rats induced upregulation of NGF in hindpaw skin and tibia bone, as well as sciatic nerve neuropeptide content.[45]

NGF is secreted by target tissues (such as macrophages and Schwann cells following nerve injury, and by basal keratinocytes in the skin), and regulates the excitability of nociceptor fibers by altering the expression of key sodium channels, receptors and neuropeptides involved in the transmission of pain stimuli.[46] Local or systemic administration of NGF in rodents has been shown to induce acute thermal hyperalgesia and delay mechanical hyperalgesia, suggesting that NGF itself is sufficient to elicit hyperalgesia.[47,48] In addition, injection of NGF into the neck muscles of mice evoked neuronal activation in areas of the brainstem and cervical spinal cord that are involved in the processing of deep noxious input,[49] indicating that NGF has a role in the pathophysiology of neck muscle nociception. In humans, intravenous or intramuscular injection of low-dose NGF (1 μg/kg) resulted in widespread pain in deep tissues and hyperalgesia at the injection site.[50,51] Systemic or local blockade of NGF bioactivity, however, inhibited the effects of inflammation on the sensitivity of sensory neurons.[48]

Nociceptive nerve ingrowth into the usually aneural inner parts of painful lumbar intervertebral discs is a known cause of discogenic back pain; accumulating evidence suggests that NGF-induced nerve growth could have a key role in the pathophysiology of inflammatory back pain. A localization study showed a causal link between substance-P-positive, CGRP-positive nociceptive nerve ingrowth into the painful disc and NGF produced by blood vessels growing into the disc from adjacent vertebral bodies.[52]

In addition, inflammatory back pain in the lumbar facet joints has been associated with increased numbers of BDNF-positive neurons and the phenotypic switch to large neurons innervating these joints in rats.[53] BDNF-positive small dorsal root ganglion (DRG) neurons have an important neuromodulatory role in inflammatory conditions; therefore, the presence of BDNF immunoreactivity in DRG neurons innervating the intervertebral disc suggests that, under physiological conditions, these DRG sensory neurons can transmit inflammatory pain from the intervertebral disc.[54] Furthermore, constitutive NGF expression in cultured human intervertebral disc cells was increased in the presence of the proinflammatory cytokines interleukin-1β and tumor necrosis factor.[55] Similarly, cultured lumbar NGF-sensitive DRG neurons exhibited increased axonal growth potential in response to neuronal injury in the presence of tumor necrosis factor.[56]

These studies suggest that, apart from being involved in the pathophysiology of neuropathic pain following nerve and peripheral tissue injury, neurotrophins have an important role in the development of injury-induced or inflammation-induced back pain.

Possible Mechanisms of Action of NGF in Bone-Injury-Induced Pain

Although the potential pathophysiological mechanisms of NGF in bone-injury-induced pain remain unclear, the studies discussed above suggest that the ensuing inflammation triggers a cascade of proinflammatory cytokine upregulation, which in turn increases NGF synthesis in macrophages, chondrocytes, fibroblasts and osteoblasts at the site of injury (Figure 1). NGF released from these cells might then directly or indirectly act on sensory neurons, resulting in pain. NGF activates TrkA on sensory nerves, upregulating the expression of pronociceptive molecules, such as capsaicin receptor (TRPV1), BDNF, and neuropeptides (substance P and CGRP), in sensory neurons, which mediate nociception via peripheral and central mechanisms. NGF also causes pain indirectly by activating TrkA on mast cells, which release a variety of nociceptive activators such as neuropeptides.[47] Furthermore, NGF can activate TrkA on sympathetic neurons, which triggers sprouting of sympathetic nerves and the release of catecholamines, which interact with sensory neurons and cause ectopic nerve firing. Nociceptive activators produced from central or peripheral routes might act upon nociceptive sensory neurons, causing the release of neurotransmitters in the dorsal horn, which in turn sensitize spinal cord neurons and transmit pain after a bone injury. Bone-injury-induced pain might, therefore, be mediated by increased nociception due to the actions of NGF on both the peripheral and central nervous pathways.

Potential functions and mechanisms of action of NGF in the development of post-injury pain. Inflammatory cells or bone healing cells at the fracture site upregulate NGF, which can act on sensory neurons directly or indirectly, resulting in pain. NGF activates its receptor (TrkA) on sensory nerves, which upregulates the expression of pronociceptive molecules, such as BDNF and neuropeptides (e.g. SP and CGRP) in sensory neurons, which mediate nociception via peripheral and central mechanisms. In addition, NGF can cause pain indirectly by activating TrkA on mast cells (which release a variety of nociceptive activators) and on sympathetic neurons. Abbreviations: BDNF, brain-derived neurotrophic factor; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglion; NGF, nerve growth factor; SP, substance P; TrkA, receptor tyrosine kinase A.

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