Abstract
Skin incision and nerve injury both induce painful conditions. Incisional and postsurgical
pain is believed to arise primarily from inflammation of tissue and the subsequent
sensitization of peripheral and central neurons. The role of axonal regeneration-related
processes in development of pain has only been considered when there has been injury
to the peripheral nerve itself, even though tissue damage likely induces injury of
resident axons. We sought to determine if skin incision would affect expression of
regeneration-related genes such as activating transcription factor 3 (ATF3) in dorsal
root ganglion (DRG) neurons. ATF3 is absent from DRG neurons of the normal adult rodent,
but is induced by injury of peripheral nerves and modulates the regenerative capacity
of axons. Image analysis of immunolabeled DRG sections revealed that skin incision
led to an increase in the number of DRG neurons expressing ATF3. RT-PCR indicated
that other regeneration-associated genes (galanin, GAP-43, Gadd45a) were also increased,
further suggesting an injury-like response in DRG neurons. Our finding that injury
of skin can induce expression of neuronal injury/regeneration-associated genes may
impact how clinical postsurgical pain is investigated and treated.
Perspective
Tissue injury, even without direct nerve injury, may induce a state of enhanced growth
capacity in sensory neurons. Axonal regeneration-associated processes should be considered
alongside nerve signal conduction and inflammatory/sensitization processes as possible
mechanisms contributing to pain, particularly the transition from acute to chronic
pain.
Key words
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References
- Chronic postoperative pain: The case of inguinal herniorrhaphy.Br J Anaesth. 2005; 95: 69-76
- Reinnervation of experimental superficial wounds in rats.Plast Reconstr Surg. 1987; 79: 595-599
- NGF and GDNF ameliorate the increase in ATF3 expression which occurs in dorsal root ganglion cells in response to peripheral nerve injury.Eur J Neurosci. 2004; 19: 1437-1445
- Transgenic over-expression of galanin in injured primary sensory neurons.Neuroreport. 2002; 13: 2129-2132
- Selective up-regulation of the growth arrest DNA damage-inducible gene Gadd45 alpha in sensory and motor neurons after peripheral nerve injury.Eur J Neurosci. 2003; 18: 911-922
- Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons.Nat Neurosci. 2001; 4: 38-43
- Triggering genetically-expressed transneuronal tracers by peripheral axotomy reveals convergent and segregated sensory neuron-spinal cord connectivity.Neuroscience. 2009; 163: 1220-1232
- Preventive analgesia to reduce wound hyperalgesia and persistent postsurgical pain: Not an easy path.Anesthesiology. 2005; 103: 681-683
- Inducible galanin and GalR2 receptor system in motor neuron injury and regeneration.J Neurochem. 1998; 71: 879-882
Cerfolio RJ, Price TN, Bryant AS, Sale Bass C, Bartolucci AA: Intracostal sutures decrease the pain of thoracotomy. Ann Thorac Surg 76:407–411;discussion 411-412, 2003
- GAP-43 mRNA in rat spinal cord and dorsal root ganglia neurons: Developmental changes and re-expression following peripheral nerve injury.Eur J Neurosci. 1992; 4: 883-895
- Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury.BMC Neurosci. 2002; 3: 16
- Regeneration of primary sensory neurons.Pharmacology. 2003; 67: 169-181
- Reduction of postincisional allodynia by subcutaneous bupivacaine: Findings with a new model in the hairy skin of the rat.Anesthesiology. 2005; 103: 113-125
- Altered cutaneous nerve regeneration in a simian immunodeficiency virus/macaque intracutaneous axotomy model.J Comp Neurol. 2009; 514: 272-283
- The neurobiology of pain: Developmental aspects.Neuroscientist. 2001; 7: 246-257
- The development of nociceptive circuits.Nat Rev Neurosci. 2005; 6: 507-520
- Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR).Pain. 2008; 135: 119-130
- Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression.Exp Neurol. 2007; 205: 347-359
- Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity.Proc Natl Acad Sci U S A. 2000; 97: 11563-11568
- Use of genetically engineered transgenic mice to investigate the role of galanin in the peripheral nervous system after injury.Neuropeptides. 2005; 39: 191-199
- Neurite outgrowth and GAP-43 mRNA expression in cultured adult rat dorsal root ganglion neurons: Effects of NGF or prior peripheral axotomy.J Neurosci Res. 1994; 39: 634-645
- Distinct functional types of macrophage in dorsal root ganglia and spinal nerves proximal to sciatic and spinal nerve transections in the rat.Exp Neurol. 2003; 184: 590-605
- Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: increased expression of ATF-3 and pharmacological characterisation.Pain. 2007; 128: 272-282
- Sensory neurons and their supporting cells located in the trigeminal, thoracic and lumbar ganglia differentially express markers of injury following intravenous administration of paclitaxel in the rat.Neurosci Lett. 2006; 405: 62-67
- Pre-emptive analgesia: evidence, current status and future directions.Eur J Anaesthesiol Suppl. 1995; 10: 8-13
- Current status of preemptive analgesia.Curr Opin Anaesthesiol. 2002; 15: 435-441
- Transition from acute to chronic postsurgical pain: Risk factors and protective factors.Expert Rev Neurother. 2009; 9: 723-744
- Mechanisms of enhancement of neurite regeneration in vitro following a conditioning sciatic nerve lesion.J Comp Neurol. 1998; 391: 11-29
- Perioperative pain.Curr Opin Anaesthesiol. 2006; 19: 556-561
- Peripheral nerve regeneration.Neurosurg Clin N Am. 1991; 2: 31-42
- NFIL3 and cAMP response element-binding protein form a transcriptional feedforward loop that controls neuronal regeneration-associated gene expression.J Neurosci. 2009; 29: 15542-15550
- The induction of pain: An integrative review.Prog Neurobiol. 1999; 57: 1-164
- Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections.J Comp Neurol. 1995; 361: 404-416
- NeuN, a neuronal specific nuclear protein in vertebrates.Development. 1992; 116: 201-211
- Sustaining intrinsic growth capacity of adult neurons promotes spinal cord regeneration.Proc Natl Acad Sci U S A. 2005; 102: 16848-16852
- Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats.Pain. 2003; 101: 65-77
- Chronic pain as an outcome of surgery. A review of predictive factors.Anesthesiology. 2000; 93: 1123-1133
- Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain.Exp Neurol. 2005; 193: 85-100
- Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells.Exp Neurol. 2007; 203: 42-54
- An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat.Brain Res. 2007; 1168: 46-59
- Distribution of P2X1, P2X2, and P2X3 receptor subunits in rat primary afferents: Relation to population markers and specific cell types.J Chem Neuroanat. 2000; 20: 141-162
- The many functions of nerve growth factor: Multiple actions on nociceptors.Neurosci Lett. 2004; 361: 168-171
- Reversal of neurochemical changes and pain-related behavior in a model of neuropathic pain using modified lentiviral vectors expressing GDNF.Mol Ther. 2006; 13: 1101-1109
- Postoperative pain–clinical implications of basic research.Best Pract Res Clin Anaesthesiol. 2007; 21: 3-13
- Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia.Curr Top Med Chem. 2005; 5: 547-555
- A role for cAMP in regeneration during development and after injury.Prog Brain Res. 2002; 137: 381-387
- Peripherin and ATF3 genes are differentially regulated in regenerating and non-regenerating primary sensory neurons.Brain Res. 2009; 1310: 1-7
- Models and mechanisms of hyperalgesia and allodynia.Physiol Rev. 2009; 89: 707-758
- Pathophysiology of complex regional pain syndrome.Expert Rev Neurother. 2006; 6: 669-681
- The transcription factor ATF-3 promotes neurite outgrowth.Mol Cell Neurosci. 2006; 32: 143-154
- ATF3 increases the intrinsic growth state of DRG neurons to enhance peripheral nerve regeneration.J Neurosci. 2007; 27: 7911-7920
- ATF3 expression in L4 dorsal root ganglion neurons after L5 spinal nerve transection.Eur J Neurosci. 2006; 23: 365-373
- cAMP and cGMP contribute to sensory neuron hyperexcitability and hyperalgesia in rats with dorsal root ganglia compression.J Neurophysiol. 2006; 95: 479-492
- Identification of candidate transcriptional modulators involved in successful regeneration after nerve injury.Eur J Neurosci. 2007; 25: 3629-3637
- The axotomy-induced neuropeptides galanin and pituitary adenylate cyclase-activating peptide promote axonal sprouting of primary afferent and cranial motor neurones.Eur J Neurosci. 2006; 24: 1555-1564
- Dermatomes in the rat limbs as determined by antidromic stimulation of sensory C-fibers in spinal nerves.Pain. 1996; 67: 197-202
- Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury.Mol Cell Neurosci. 2000; 15: 170-182
- Peripheral sensory axon growth: from receptor binding to cellular signaling.Can J Neurol Sci. 2008; 35: 551-566
- Glial cell line-derived neurotrophic factor normalizes neurochemical changes in injured dorsal root ganglion neurons and prevents the expression of experimental neuropathic pain.Neuroscience. 2003; 121: 815-824
- NeuN: A useful neuronal marker for diagnostic histopathology.J Histochem Cytochem. 1996; 44: 1167-1171
- Expression profile of nerve growth factor after muscle incision in the rat.Anesthesiology. 2009; 110: 140-149
- Targeted disruption of the murine galanin gene.Ann N Y Acad Sci. 1998; 863: 22-47
- Comparison of skin incision vs. skin plus deep tissue incision on ongoing pain and spontaneous activity in dorsal horn neurons.Pain. 2009; 144: 329-339
- Separate groups of dorsal horn neurons transmit spontaneous activity and mechanosensitivity one day after plantar incision.Eur J Pain. 2009; 13: 820-828
- Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision.Anesthesiology. 2010; 112: 153-164
- Mechanisms for pain caused by incisions.Reg Anesth Pain Med. 2002; 27: 514-516
- Synaptic modulation in pain pathways.Rev Physiol Biochem Pharmacol. 2005; 154: 73-100
- Expression of peptides, nitric oxide synthase and NPY receptor in trigeminal and nodose ganglia after nerve lesions.Exp Brain Res. 1996; 111: 393-404
Article info
Publication history
Published online: June 02, 2010
Accepted:
February 1,
2010
Received in revised form:
January 26,
2010
Received:
January 6,
2010
Footnotes
Caitlin E. Hill and Benjamin J. Harrison contributed equally to this work.
Supported in part by funding from NIH (NS16996 – L.M.M., RR015576 – J.C.P.), The Christopher and Dana Reeve Foundation International Consortium on Spinal Cord Injury Research (L.M.M., M.B.B.), the Paralyzed Veterans of America (Fellowship – B.J.H.), the Kentucky Spinal Cord and Head Injury Research Trust (J.C.P.), Miami Project to Cure Paralysis (M.B.B.).
Identification
Copyright
© 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.
