Controlled release of GDNF reduces nerve root‐mediated behavioral hypersensitivity

Abstract

Nerve root compression produces persistent behavioral sensitivity in models of painful neck injury. This study utilized degradable poly(ethylene glycol) hydrogels to deliver glial cell line-derived neurotrophic factor (GDNF) to an injured nerve root. Hydrogels delivered $98% of encapsulated GDNF over 7 days in an in vitro release assay without the presence of neurons and produced enhanced outgrowth of processes in cortical neural cell primary cultures. The efficacy of a GDNF hydrogel placed on the root immediately after injury was assessed in a rat pain model of C7 dorsal root compression. Control groups included painful injury followed by: (1) vehicle hydrogel treatment (no GDNF), (2) a bolus injection of GDNF, or (3) no treatment. After injury, mechanical allodynia (n ¼ 6/group) was significantly decreased with GDNF delivered by the hydrogel compared to the three injury control groups (p < 0.03). The bolus GDNF treatment did not reduce allodynia at any time point. The GDNF receptor (GFRa-1) decreased in small, nociceptive neurons of the affected dorsal root ganglion, suggesting a decrease in receptor expression following injury. GDNF receptor immunoreactivity was significantly greater in these neurons following GDNF hydrogel treatment relative to GDNF bolus treated and untreated rats (p < 0.05). These data suggest efficacy for degradable hydrogel delivery of GDNF and support this treatment approach for nerve root-mediated pain. Keywords: radiculopathy; neurotrophic factor; GDNF; hydrogel; allodynia Chronic neck pain affects as many as 71% of adults at some point during their lives. 1,2 Painful cervical spine injuries can result from nonphysiologic loading of the neck as occurs in recreational accidents and contact sports, 3,4 when nerve roots can be compressed. 5 Nerve root compression induces persistent behavioral hypersensitivity in rat models of radiculopathy, in which painful responses are elicited in the affected dermatome by stimulation that does not normally provoke pain (mechanical allodynia). [6][7][8][9] Further, hypersensitivity to a stimulus has been used as a sensitive clinical indicator of pain. 10 Compression of primary afferent neurons also produces increased neuronal excitability, ectopic axonal firing, Wallerian degeneration, endoneurial edema, inflammatory responses, and decreased spinal substance P. 7,8,[11][12][13][14][15][16] Current treatments for neuropathic pain include opioids, nonsteroidal anti-inflammatories, antagonists to ion channels, neuropeptides, cytokines, and trophic factors to promote cell survival and regeneration. [17][18][19][20][21][22][23] Neurotrophic factors can prevent secondary neuronal degeneration and reduce spontaneous firing. In particular, glial cell line-derived neurotrophic factor (GDNF) has analgesic effects and modulates nociceptive signaling by altering sodium channel subtype expression and reducing aberrant A-fiber sprouting into the cord. 18,19,[24][25][26] However, in neuropathic pain models, GDNF is decreased after injury which may initiate ...

Cytokine Antagonism Reduces Pain and Modulates Spinal Astrocytic Reactivity After Cervical Nerve Root Compression

“…18 As such, determining whether common cytokines are key regulators in these types of painful injuries would provide potentially valuable avenues for drug development in treating chronic pain. TNFa antagonists, such as infliximab and the soluble TNF receptor-1 (sTNFR1), reduce behavioral hypersensitivity when given in pretreatment or perioperative paradigms, with less robust effects when given after the onset of symptoms.…”

The potential for salmon fibrin and thrombin to mitigate pain subsequent to cervical nerve root injury

“…While the exact mechanism of action by which salmon fibrin and thrombin reduce pain is still unknown, the current findings do support previous work with varied therapeutic approaches for eliminating pain by the administration of pharmacologic formulations at the site of injury. For example, a hydrogel with controlled release of glial cell line-derived neurotrophic factor placed at the root or early intervention with local administration of the soluble TNF-α receptor to the injured nerve root attenuated both allodynia and the associated inflammatory responses in the DRG [16, 20]. Taken together with the results of this current study, it is likely that biomaterials that provide sustained delivery of anti-inflammatory and neural cell promoting factors provide the best promise for treating pain from neural trauma.…”

“…A painful transient nerve root compression was applied to the right C7 cervical dorsal nerve root [9–12, 16, 19, 20, 22]. All surgical procedures were performed under isoflurane inhalation anesthesia (4% for induction, 2% for maintenance).…”

“…In order to completely expose the nerve root, a small incision was made in the dura at the dorsal root’s insertion into the spinal cord [9]. The right C7 dorsal nerve root was compressed for 15 minutes using a 10 gram-force microvascular clip (World Precision Instruments; Sarasota, FL) [9–12, 16, 19, 20, 22]. Salmon fibrin (20 μl) was administered directly to the C7 nerve root immediately after the microvascular clip was removed and the fibrin gel was allowed to polymerize in vivo (n=6, fibrin ).…”

A drug delivery hydrogel system based on activin B for Parkinson's disease

“…A C C E P T E D ACCEPTED MANUSCRIPT 4 cross-linked heparin and star-PEG for neuronal cell replacement strategies in Parkinson's or Huntington's disease treatment has been reported [24]; also, it is found that hydrogel delivery provides significant trophic support to damaged primary afferents and is a promising treatment modality for nerve root compression-mediated pain [25]. Hydrogels are mainly composed of crosslinked hydrophilic macromolecules with water-swollen properties [26].…”