Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy
Introduction
Neuropathic pain is a dysfunctional and debilitating pain that remains intractable to most current treatment strategies (Finnerup et al., 2007, Hawksley, 2006, Vissers, 2006). The etiology of neuropathic pain is varied in that the causes can include infection (e.g. varicella-zoster virus leading to post-herpetic neuralgia, neuritis, HIV), metabolic disorders (e.g. diabetes, vitamin deficiency), toxins/drugs (e.g. chemotherapy), autoimmune disease (e.g. Guillain–Barre syndrome), and physical trauma to the nerve and other structures. Neuropathic pain is distinguishable from acute pain in that it may be exaggerated (hyperalgesia), provoked by innocuous stimulation (dysesthesia, allodynia), and/or occurs spontaneously. It is commonly thought that pain resulting from peripheral neuropathy is triggered by discharge in the freshly injured nerve that generates multiple pathophysiological, transcriptional, translational, neurochemical, and structural changes in sensory processing in pain pathways. The current state of understanding of this type of pain is that ectopic discharge from both damaged and also neighboring intact/surviving primary afferent fibers, produced by the effects of Wallerian degeneration (Obata et al., 2004), develops (Devor and Wall, 1990, Kovalsky et al., 2008, Lee et al., 2003, Li et al., 2000, Obata et al., 2003, Wu et al., 2002, Yoon et al., 1996), and elevates discharge of spinal nociceptive neurons (Pitcher and Henry, 2000, Pitcher and Henry, 2004, Sotgiu et al., 1995a), inducing changes in sensory processing in the spinal dorsal horn and in supraspinal structures.
There is a lack of consensus, however, regarding the locus of the governing change that maintains neuropathic pain and, in fact, different components of the somatosensory axis have been proposed to maintain this pain. One hypothesis suggests that central sensitization at the level of the spinal dorsal horn is maintained independently of primary afferent input (Sandkuhler and Liu, 1998) since input from the periphery is reportedly insufficient to maintain spinal modifications in sensory processing and ultimately neuropathic pain (Burgess et al., 2002, Sun et al., 2005, Xie et al., 2005). Another view suggests that mechanisms at the spinal dorsal horn level require continuous facilitatory input from supraspinal structures (Bian et al., 1998, Carlson et al., 2007, Gardell et al., 2003, Kauppila et al., 1998, Kovelowski et al., 2000, Ossipov et al., 2000, Pertovaara et al., 1997, Pertovaara et al., 2001, Porreca et al., 2001, Saade et al., 2006a, Saade et al., 2006b, Saade et al., 2007, Suzuki et al., 2002, Suzuki et al., 2004a, Suzuki et al., 2004b, Vera-Portocarrero et al., 2006).
However, in both animal models and humans effects of peripheral neuropathy including peripheral neurodegeneration, altered Na+ and K+ ion channel expression (Coward et al., 2001a, Coward et al., 2001b, Hong et al., 2004, Hong and Wiley, 2006, Joshi et al., 2006, Matthews et al., 2006, Shembalkar et al., 2001), and abnormal impulse discharge (Nordin et al., 1984, Nystrom and Hagbarth, 1981) in sensory afferents have been shown to persist several weeks/months (Casula et al., 2004, Coward et al., 2000, Fried et al., 1991, Kretschmer et al., 2002, Lin et al., 2001, Pan et al., 2001, Pertin et al., 2005, Roytta et al., 1999, Seltzer et al., 1991b). This raises the question what role, if any, do such multiple and long lasting modifications in peripheral sensory input play in maintaining the persistent changes in the central nervous system and in neuropathic pain?
In earlier studies on a rat model of neuropathic pain, in which a polyethylene cuff had been placed around the sciatic nerve, we observed spontaneous pain and tactile hypersensitivity that lasted several weeks (Pitcher et al., 1999a). Electrophysiological recordings made in the same neuropathic animals showed a gain in rate of spontaneous on-going discharge of wide dynamic range (WDR) dorsal horn neurons and gain in magnitude and duration of the afterdischarge of these neurons in response to stimulation of the peripheral cutaneous receptive field at the same time points weeks after cuff implantation correlating with neuropathic pain behaviors (Pitcher and Henry, 2000, Pitcher and Henry, 2004). This increased excitation of WDR neurons was not mediated by descending supraspinal input as the rats in these experiments were spinalized. What was not clear was whether this increased excitation was due to post-synaptic changes in the spinal dorsal horn or whether it was maintained by abnormal input from primary afferents. Thus, the present study was aimed to answer whether primary afferent input at time points well after the onset of peripheral neuropathy (i.e. several weeks) plays a role in mediating increased excitation of spinal dorsal horn neurons. We investigated this by recording from single lumbar nociceptive dorsal horn neurons in spinalized cuff-implanted rats and applying lidocaine directly to the sciatic nerve during spontaneous on-going activity or during the afterdischarge provoked by mechanical cutaneous stimulation of the cuff-implanted hind paw. We provide evidence that hyperexcited nociceptive dorsal horn neurons in rats with chronic peripheral neuropathy is reversed by application of lidocaine to the sciatic nerve proximal as well as distal to the cuff.
Section snippets
Materials and methods
Experiments were done using adult, male Sprague–Dawley rats (375–425 g) from Harlan Sprague Dawley, Inc. (Indianapolis, Indiana, USA). They were housed in plastic cages containing wood chip bedding (Hardwood Laboratory Bedding, Northeastern Products Corp., Warrensburg, NY, USA) and maintained on a 12:12 h light:dark cycle (lights on at 07:00 h) with access to food and water ad libitum. Guidelines in The Care and Use of Experimental Animals by the Canadian Council on Animal Care were followed
Results
All cuff-implanted rats used in this study exhibited increased tactile sensitivity in the von Frey filament test from day 14 and onward (data not shown) similar to that reported previously (Pitcher et al., 1999a, Pitcher and Henry, 2000, Pitcher and Henry, 2004).
Discussion
This study demonstrates that local anesthetic block of the sciatic nerve in the cuff model of peripheral neuropathy in rats reverses the abnormally increased spontaneous on-going discharge activity in lumbar dorsal horn WDR neurons and also reverses the abnormally exaggerated afterdischarge of these neurons following a noxious mechanical stimulus to the hind paw cutaneous receptive field. The data thus suggest that a constitutively active afferent input originating from multiple ectopic regions
Acknowledgments
This study was supported by grants from the Canadian Institutes of Health Research to JLH. GMP was a student supported by awards from the Royal Victoria Hospital Research Institute, the McGill Faculty of Medicine, and the Fonds pour la formation de chercheurs et l'aide a la recherche (Province of Quebec). The authors are grateful to Dr. Ze'ev Seltzer for critical reading of the manuscript and to Jennifer Ritchie for excellent technical assistance.
References (160)
- et al.
Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome
Pain
(2006) - et al.
Multiple phases of relief from experimental mechanical allodynia by systemic lidocaine: responses to early and late infusions
Pain
(2003) - et al.
Loss of spinal mu-opioid receptor is associated with mechanical allodynia in a rat model of peripheral neuropathy
Pain
(2006) - et al.
Tactile allodynia, but not thermal hyperalgesia, of the hindlimbs is blocked by spinal transection in rats with nerve injury
Neurosci. Lett.
(1998) - et al.
Na(v)1.7 sodium channel expression in human lingual nerve neuromas
Arch. Oral Biol.
(2007) - et al.
Can neuralgias arise from minor demyelination? Spontaneous firing, mechanosensitivity, and afterdischarge from conducting axons
Exp. Neurol.
(1982) - et al.
The effect of intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas
Pain
(1989) - et al.
Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states
Pain
(2000) - et al.
Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism
Pain
(1997) - et al.
Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction
Pain
(1992)
A comparison of the antinociceptive effects of voltage-activated Na+ channel blockers in two rat models of neuropathic pain
Eur. J. Pharmacol.
Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrollment study
Pain
Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats
Pain
Effects of prior anaesthesia on autotomy following sciatic transection in rats
Pain
Painful neuropathy: altered central processing maintained dynamically by peripheral input
Pain
Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat
J. Biol. Chem.
Altered expression and function of sodium channels in large DRG neurons and myelinated A-fibers in early diabetic neuropathy in the rat
Biochem. Biophys. Res. Commun.
Pharmacological studies on a rat model of trigeminal neuropathic pain: baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour
Pain
The role of uninjured C-afferents and injured afferents in the generation of mechanical hypersensitivity after partial peripheral nerve injury in the rat
Exp. Neurol.
Central sensitization and LTP: do pain and memory share similar mechanisms?
Trends Neurosci.
Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain
Neurobiol. Dis.
Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states
Pain
Spontaneous discharge originates in the dorsal root ganglion at the onset of a painful peripheral neuropathy in the rat
Neurosci. Lett.
Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat
Brain Res.
Cutaneous vascular responses evoked by noxious stimulation in rats with the spinal nerve ligation-induced model of neuropathy
Brain Res. Bull.
Involvement of increased excitatory amino acids and intracellular Ca2+ concentration in the spinal dorsal horn in an animal model of neuropathic pain
Pain
Dorsal column lesion reduces mechanical allodynia in the induction, but not the maintenance, phase in spinal hemisected rats
Neurosci. Lett.
Peripheral axonal injury results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord
Pain
Subthreshold oscillations facilitate neuropathic spike discharge by overcoming membrane accommodation
Exp. Neurol.
Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat
Pain
The role of uninjured nerve in spinal nerve ligated rats points to an improved animal model of neuropathic pain
Eur. J. Pain
Involvement of substance P and calcitonin gene-related peptide in development and maintenance of neuropathic pain from spinal nerve injury model of rat
Neurosci. Res.
Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers
Pain
Cutaneous nerve terminal degeneration in painful mononeuropathy
Exp. Neurol.
Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats
Pain
Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury
Pain
Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats
Pain
Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study
J. Pain
Increase of calcitonin gene-related peptide immunoreactivity in the axonal fibers of the gracile nuclei of adult and aged rats after complete and partial sciatic nerve injuries
Exp. Neurol.
Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study
Pain
Role of signals from the dorsal root ganglion in neuropathic pain in a rat model
Neurosci. Lett.
Somatosensory cortical plasticity in carpal tunnel syndrome—a cross-sectional fMRI evaluation
Neuroimage
Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves, dorsal roots and dorsal columns
Pain
Microelectrode recordings from transected nerves in amputees with phantom limb pain
Neurosci. Lett.
Contribution of degeneration of motor and sensory fibers to pain behavior and the changes in neurotrophic factors in rat dorsal root ganglion
Exp. Neurol.
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
QX-314 inhibits ectopic nerve activity associated with neuropathic pain
Brain Res.
Tetrodotoxin inhibits neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons
Pain
Mediation of spinal nerve injury induced tactile allodynia by descending facilitatory pathways in the dorsolateral funiculus in rats
Neurosci. Lett.
Chronic spinal nerve ligation induces changes in response characteristics of nociceptive spinal dorsal horn neurons and in their descending regulation originating in the periaqueductal gray in the rat
Exp. Neurol.
Cited by (70)
BDNF in Neuropathic Pain; the Culprit that Cannot be Apprehended
2024, NeuroscienceAre sensory neurons exquisitely sensitive to interleukin 1β?
2021, Journal of NeuroimmunologyCitation Excerpt :A summary and comparison of the reported effective concentrations of IL-1β on neurons and T-lymphocytes is presented in the graphical abstract. Since ongoing excitation and persistent spontaneous activity in sensory neurons plays a seminal role in the onset and persistence of neuropathic pain (Pitcher and Henry, 2008; Vaso et al., 2014; Koplovitch and Devor, 2018; Liu et al., 2001; Alles and Smith, 2018; Devor, 2009; Djouhri et al., 2006; Bedi et al., 2010; Smith, 2020) and this may be the result of actions of injury-induced release of cytokines from macrophages (Kiguchi et al., 2010) and/or satellite glial cells (Takeda et al., 2008b) we asked whether DRG neurons exhibit the same exquisite sensitivity to IL-1β as hippocampal neurons and T-lymphocytes. This was done using a defined medium, neuron enriched culture system which we developed to study long term actions of IL-1β on the excitability of DRG neurons (Noh et al., 2019; Stemkowski et al., 2015; Stemkowski and Smith, 2012).
The Known Biology of Neuropathic Pain and Its Relevance to Pain Management
2024, Canadian Journal of Neurological Sciences
- 1
Present address: Michael G. DeGroote Institute for Pain Research and Care, Health Sciences Centre, Room 1J11, 1200 Main Street West, Hamilton ON, Canada L8N 3Z5. Fax: +1 905 522 8844.