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Department of Anesthesiology and Center for Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Submitted 15 June 2005; accepted in final form 26 July 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Kim et al. 1993) suggests that ongoing afferent activity, presumably abnormal activity, drives pain and hypersensitivity. Electrophysiological studies in animals indicate that axotomy of primary sensory neurons results in hyperexcitability, spontaneous activity, and capability to repetitively fire after a single depolarization to action potential (AP) threshold (Amir et al. 1999; Kajander and Bennett 1992; Kim et al. 1993; Wall and Devor 1983). These changes occur in large-diameter A fibers with a time course similar to that of allodynia and are associated with depolarized resting membrane potential (Vm), reduced AP threshold, and membrane oscillations in cell somata in the dorsal root ganglion (DRG), an important site of spontaneous activity (Campbell et al. 1988; Kajander and Bennett 1992; Liu et al. 2000, 2002b).
Although these changes in excitability after axotomy may play a role in pain and sensitization, there is also interest in whether unaxotomized primary afferents become hyperexcitable and directly mediate allodynia. To address this, recent studies have observed similar changes in unaxotomized sensory neurons whose peripheral processes intermingle with those of injured neurons (Ali et al. 1999; Boucher et al. 2000; Ma et al. 2003; Wu et al. 2001). Some authors speculate that neural and immune responses during Wallerian degeneration in the nerve result in excitability in their uninjured neighbors (Ma et al. 2003). That study, however, did not determine whether the unaxotomized neurons projected to the site of sensory testing. Additionally, they injured the nerve at a very proximal site (spinal nerve ligation). The presence and extent of many of changes in afferent excitability depend heavily on the site of nerve injury relative to the cell body (Liu et al. 2000; Ma et al. 2003). For example, distal nerve axotomy results in a larger proportion of A fibers with capability to repetitively fire, but a smaller proportion with spontaneous activity than proximal axotomy (Liu et al. 2000). The effect of distal nerve injury on unaxotomized neighboring fibers has not previously been examined. One purpose of the current study was to test whether similar changes occur in axotomized neurons and unaxotomized neurons projecting to the hindpaw (the site of behavioral testing) after nerve injury in a more peripheral location (Seltzer et al. 1990).
The 
2-adrenoceptor agonist clonidine has been approved for epidural administration in the treatment of neuropathic pain for many years, and the assumed site of action of this drug by this route is on 2-adrenoceptors in the spinal cord (Eisenach et al. 1996). Other studies have suggested a peripheral site of action. For example, transdermal clonidine reduces pain in patients with diabetic neuropathy (Zeigler et al. 1992) and postherpetic neuralgia (Kirkpatrick et al. 1992). Additionally, peripheral nerve injury results in a buildup of 2-adrenoceptors in the nerve just proximal to the site of lesion (Birder and Perl 1999; Gold et al. 1997) as well as in immune cells, primarily macrophages and T lymphocytes, surrounding the injury site and within the nerve (Lavand'homme et al. 2002). Perineural injection of clonidine at the injury site reduces hypersensitivity in the paw after partial sciatic nerve ligation (PSNL) with a delayed onset of days and a prolonged duration of weeks, and this inhibition is prevented when clonidine is coadministered with an 2-adrenoceptor antagonist (Lavand'homme et al. 2002). Clonidine-treated animals also demonstrate reduced concentrations of proinflammatory cytokines in the injured nerve and DRG at the time of clonidine's antihypersensitivity effect (Lavand'homme and Eisenach 2003). A key proinflammatory cytokine, tumor necrosis factor (TNF), sensitizes and induces spontaneous activity in primary afferents (Sorkin et al. 1997) and in DRG somata (Liu et al. 2002a), and it is conceivable that the association between reduced cytokine expression and reduced hypersensitivity after clonidine administration is linked by reduced afferent excitability. The second purpose of the current study was therefore to determine whether perineural clonidine diminished excitability after PSNL, and whether it did so similarly in unaxotomized or injured neurons.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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All experiments were approved by the Animal Care and Use Committee of Wake Forest University School of Medicine. Forty-three adult male Wistar rats (Harlan, Indianapolis, IN) were used, weighing 200–250 g on the day of the experiments. Animals were housed at 22°C and under a 12 h:12 h light:dark cycle, with free access to food and water.
Surgical preparation
PSNL was performed as previously described (Seltzer et al. 1990). Briefly, the left sciatic nerve was carefully exposed at mid thigh level. The dorsal half of the sciatic nerve was carefully separated and sectioned, and the distal part of the sectioned nerve tightly ligated using a 6/0 silk suture. The proximal part of sectioned nerve was carefully separated from the unaxotomized nerve along a 4- to 6-mm distance and the cut end was inserted into a small glass capsule filled with 10% fluororuby (Molecular Probes, Paisley, UK), dissolved in 0.9% sterile saline, wt/vol, for 10 min. The proximal end of the sectioned nerve was then tightly ligated using a 6/0 silk suture. The incision was closed in layers.
A different retrograde tracer was used to identify unaxotomized neurons in the DRG innervating the site of sensory testing. As previously described (Hudson et al. 2001), after closure of the PSNL incision, 10 µl 1% of fast blue (FB, Sigma-Aldrich, Manchester, UK), wt/vol dissolved in sterile water, were injected intradermally into the sterilized glabrous hairy border and plantar surface of the lateral aspect of the left hind paw, using a 32-g needle. Anesthesia was then discontinued.
Behavioral testing
Withdrawal threshold to punctate mechanical stimuli was determined before and on days 1, 3, 5, 7, 9, 11, 13, and 14 after peripheral nerve injury by the application of calibrated von Frey filaments (Stoelting, Wood Dale, IL). Animals were placed on a plastic mesh floor in individual clear plastic boxes and allowed to accommodate to their environment for 
30 min. The von Frey filaments were applied vertically to the plantar surface of the hindpaw ipsilateral to the partial nerve ligation, and gently pushed to the bending point. Filaments were applied three to four times. If no response was elicited, a larger-diameter filament was applied in the same manner. The filaments were applied in increasing order (0.53, 0.93, 1.14, 1.58, 2.81, 4.25, 6.58, 9.08, 11.69, 22.28, and 58.6 g) until a brisk withdrawal or paw flinching was elicited, which was considered as a positive response. The withdrawal threshold was determined using an up–down statistical method (Chaplan et al. 1994) twice, with testing separated by 10 min, and the mean withdrawal threshold was used for data analysis.
Drug administration
To determine the influence of perineural clonidine on behavior and neuronal excitability, rats with reduced withdrawal thresholds 2 wk after PSNL were briefly anesthetized and clonidine (0.3 ml, 30 µg) or saline (0.3 ml) was injected perineurally by percutaneous injection, using a fanning motion, as previously described (Thalhammer et al. 1995). In control experiments, the same dose of clonidine was injected intramuscularly to determine whether clonidine acted in a systemic manner. All injections were performed by an investigator who did not perform behavioral or electrophysiological studies, guaranteeing that these observations were obtained in a blinded manner. Withdrawal threshold was then determined 1, 2, and 3 days after perineural injection.
Microelectrode intracellular recording
Intracellular recording of DRG neurons in an isolated, whole preparation was performed as previously described (Liu et al. 2002a). Briefly, after surgical dissection, the left L4 or L5 DRGs were placed in the recording chamber and mounted on the stage of an upright microscope (BX51-WI, Olympus, Tokyo, Japan). A U-shaped stainless steel wire on which three to four fine nylon fibers spanned the two sides was used to gently hold the ganglion immersed at the bottom of the chamber. The DRG was continuously perfused with oxygenated artificial cerebrospinal fluid containing (in mM): 130 NaCl, 3.5 KCl, 1.25 NaH2PO4, 24 NaHCO3, 10 dextrose, 1.2 MgCl2, and 1.2 CaCl2 (pH = 7.3) at a rate of 3–4 ml/min, and the temperature was maintained at 37 ± 1°C.
Intracellular electrophysiological recordings were made with microelectrodes filled with 2.5 M potassium acetate (pH = 7.2). Satisfactory recordings were obtained with electrodes of 50–80 M
. Before electrode penetration, the DRG soma was viewed with a CCD camera combined with infrared DIC or fluorescence microscopy. Only neurons identified as axotomized, which contained fluororuby, or unaxotomized and innervating the hindpaw, which contained FB, were studied. Somata of DRG were visually classified according to diameter as small (
30 µm), medium (30–49 µm), or large (50 µm) as previously described in this preparation (Liu et al. 2002a). Electrophysiological data were collected with the use of single-electrode continuous current clamp (AxoClamp-2B, Axon Instruments, Foster City, CA) and analyzed with Clampex 8 software (Axon Instruments).
Membrane properties and AP parameters were measured as previously reported (Czeh et al. 1977; Liu et al. 2002a; Zhang et al. 1999), including Vm, voltage and current thresholds, whole cell input resistance (Rin), and afterhyperpolarization (AHP). Depolarizing currents of 0.05–4.0 nA (100-ms pulse duration) were delivered in increments of 0.05 nA until an AP was evoked. The threshold current (rheobase) was defined as the minimum current required to evoke an AP. The AP voltage threshold was defined as the first point on the rising phase of the spike at which the change in voltage exceeded 50 mV/ms. The duration of the AP (APD) was measured at the AP threshold level. The AP amplitude was measured between the peak and the AP threshold. The Rin for each cell was obtained from the slope of a steady-state I–V plot in response to a series of hyperpolarizing currents of 100-ms duration, delivered in decreasing steps of 0.05 nA from 0.2 to –2 nA. The AHP amplitude was measured from the valley peak to the baseline and the AHP duration was measured at amplitude halfway between.
For each neuron, a continuous recording was obtained for 3 min after electrode penetration. Only neurons with stable resting membrane potential were studied. Cells were considered to show oscillations if, before action potential recording, they displayed increasing and decreasing potential >1.5 times resting threshold, and were considered to show spontaneous activity if they exhibited any action potentials in 3 min of continuous recording in the absence of a stimulus. Capability for repetitive firing and the number of volleys were determined by injection of a depolarizing current with amplitude 1.5 times the rheobase and of 100-ms duration.
Statistical analyses
Data are presented as means ± SE. Student's t-test or two-way ANOVAs were used to compared groups or times with withdrawal threshold and membrane and AP properties. 
2 or Fisher's exact test were used to compare groups for the incidence of cells expressing membrane oscillation, accommodation, and spontaneous activity. P < 0.05 was considered significant.
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RESULTS |
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The mean paw withdrawal threshold to von Frey filament testing did not differ between sham and PSNL groups before surgery. The overall mean paw withdrawal threshold at this time was 22 ± 1.7 g. After surgery, the withdrawal threshold did not change in the sham group. In contrast, paw withdrawal threshold 14 days after PSNL was dramatically reduced to 1.8 ± 0.2 g. A single perineural injection of saline 0.3 ml did not change the withdrawal threshold 3 days after injection (n = 12). In contrast, a single perineural injection of clonidine, 30 µg, significantly increased withdrawal threshold 3 days later to 8.5 ± 0.4 g, although this value was still significantly lower than the pre-PSNL baseline (n = 11, Fig. 1). A single intramuscular injection of the same dose of clonidine failed to alter withdrawal threshold, which was 1.0 ± 0.05 before and 1.4 ± 0.1 g 3 days after clonidine injection.
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Intracellular recordings were obtained from a total of 387 neurons. Of these, 89 were from the sham group, 134 were from the PSNL plus perineural saline group, 129 were from the PSNL plus perineural clonidine group, and 35 were from the PSNL plus systemic clonidine group.
Perineural injections
LARGE-DIAMETER DRG NEURONS. Axotomized and unaxotomized large-diameter neurons in the PSNL plus perineural saline group differed in membrane properties compared with the sham group in a largely similar, but not identical manner. As such, both axotomized and unaxotomized large-diameter neurons after PSNL had more depolarized Vm, lower voltage and current thresholds, larger APD, increased Rin, and slower rising and falling phases of the AP than those of large-diameter neurons in the sham group. There were, however, some significant differences after PSNL in large-diameter unaxotomized versus injured neurons. Thus unaxotomized large-diameter neurons demonstrated a shorter APD (1.5 ± 0.09 ms) and slower falling phase of AP (–101 ± 8.6 mV/ms) than axotomized large-diameter neurons (2.2 ± 0.1 ms and –69.6 ± 4.5 mV/ms, respectively).
Perineural clonidine reversed or partially reversed many of the membrane and AP properties in large-diameter DRG neurons. Thus clonidine reversed the effect of PSNL on Vm in both unaxotomized and axotomized neurons, reversed the effect on voltage threshold, and partially reversed the effect on rheobase (Table 1). In contrast, neurons from clonidine-treated animals did not differ from perineural saline control neurons in APD, Rin, and the rising and falling rates of the AP in large-diameter neurons (Table 1).
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SMALL-DIAMETER DRG NEURONS. The effects of PSNL on unaxotomized and axotomized small-diameter neurons were less pronounced than those of large-diameter neurons, but clear effects were observed. Thus although small-diameter neurons from PSNL plus perineural saline did not differ from sham in Vm, both unaxotomized and axotomized small-diameter neurons had significantly decreased voltage and current thresholds (Table 3). There were some significant differences after PSNL in small-diameter unaxotomized versus injured neurons. Unaxotomized small-diameter neurons demonstrated a slower falling phase of AP (–45.2 ± 3.05 mV/ms) than that of axotomized small-diameter neurons (–35.2 ± 1.58 mV/ms).
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MEMBRANE POTENTIAL OSCILLATIONS. Membrane potential oscillation was assessed in a total of 335 neurons. Of the 56 neurons from sham group, only two (3%) exhibited oscillations. In contrast, 28% of axotomized and 18% of unaxotomized neurons after PSNL plus perineural saline demonstrated oscillations (P < 0.05 compared with sham; Fig. 2). The proportion of unaxotomized and axotomized neurons with oscillations after perineural clonidine treatment remained greater than that of sham, but was reduced in axotomized neurons compared with PSNL plus saline control (Fig. 2). Thus clonidine treatment resulted in a partial reduction in the proportion of neurons with membrane oscillations after PSNL.
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To determine whether the reduced excitability by clonidine arose from a local or systemic action, some PSNL animals received a systemic injection of clonidine and DRGs were studied 3 days later. In contrast to perineural administration, discussed in the preceding paragraphs, intramuscular clonidine failed to alter membrane properties of axotomized large-, medium-, or small-diameter neurons after PSNL (Table 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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), by demonstrating extensive changes in small-diameter neurons and by specifically examining unaxotomized neurons that innervate the area of hypersensitivity. Second, these results confirm previous observations of a curiously delayed onset of reversal of hypersensitivity after PSNL by perineural but not systemic clonidine injection (Lavand'homme et al. 2002) and extend them by demonstrating an associated reduction in excitability of sensory neurons. This reduced excitability after clonidine treatment was interestingly similar in all cell sizes and in unaxotomized neurons innervating the testing site as well as axotomized neurons. A discussion of the essential limitations of these observations is introduced next, followed by interpretation of these two novel findings.
Several factors limit interpretation of the current study. The dose of perineural clonidine and timing of DRG removal were based on our previous observations of dose and time responses of perineural clonidine to coincide with clonidine's maximal dose and peak effect (Lavand'homme et al. 2002). We recognize that examining a range of doses and times would further strengthen the confidence in the association between clonidine's effect on behavior and neurophysiologic properties. We also recognize that the percutaneous method of perineural injection does not guarantee administration of the drug close to the nerve. This method, however, results in flaccid paralysis of the hindlimb in >95% of injections of local anesthetic (Lavand'homme et al. 2002), suggesting it is reasonably reliable. Removal of the entire DRG is not as destructive as acute dissociation, in that it maintains the anatomy of cell–cell contacts between neurons and support cells and does not require enzymatic digestion of tissue, but does nonetheless produce an axotomy in all DRG neurons. We believe the results obtained in the current study are likely to reflect cell properties in vivo because DRG neurons were studied within a few hours of this axotomy, before electrophysiologic changes are commonplace (Liu et al. 2000) and because even acutely dissociated sensory neurons exhibit many of the nerve injury–induced changes as those recorded in vivo (Ma et al. 2003). We recognize that we cannot determine the conduction velocity or fiber type of DRG neurons by measuring cell diameter. Nonetheless, the categorization we used in the current study of large-, medium-, and small-diameter neurons correlates remarkably well with A
, A
, and C neurons, respectively, as determined by measuring conduction velocity in vivo (Ma et al. 2003). Finally, we recognize that membrane depolarization itself can induce oscillations and spontaneous firing in normal sensory neurons (Amir et al. 1999), although oscillations occur at more depolarized potentials than seen in our neurons from PSNL animals, and spontaneous firing is very rare in normal sensory neurons.
Distal peripheral injury–induced changes in excitability extend to small-diameter sensory afferents
Nerve injury–induced changes in membrane properties, primarily depolarized Vm, decreased rheobase, and altered AP properties (increased APD and capability for repetitive firing), that were observed in the current study are typical of numerous previous reports after axotomy (Kajander and Bennett 1992; Kim et al. 1993; Liu et al. 2000; Wall and Devor 1983) and in neighboring unaxotomized neurons (Ali et al. 1999; Boucher et al. 2000; Ma et al. 2003; Wu et al. 2001). The current study extends these previous observations by indicating that unaxotomized and axotomized neurons change in a similar manner with respect to membrane properties and excitability after this more distal nerve injury. In contrast to proximal injury (Ma et al. 2003), however, membrane properties were more severely affected in small- and medium-diameter unaxotomized and axotomized neurons after more distal peripheral nerve injury in the current study. As such, AP threshold and rheobase were reduced in unaxotomized medium- and small-diameter sensory neurons in the current study with peripheral injury, but these parameters were unaffected after proximal injury (Ma et al. 2003). Whether these differences in unaxotomized neurons between the two studies reflect proximal versus distal injury or different inclusion criteria (selectively those innervating the paw in the current study) cannot be determined from these experiments.
The role of small-diameter DRG neurons, presumably most of which are C fibers, to ongoing pain and hypersensitivity after peripheral nerve injury is controversial, and may vary with the type of nerve injury. For example, chronic constriction injury of the mid sciatic nerve results in a maintenance of C fibers and pronounced thermal hypersensitivity (Laird and Bennett 1993), whereas spinal nerve ligation may result in loss of C fibers, at least in the ligated nerves, and more pronounced mechanical than thermal hypersensitivity (Röyttä et al. 1999). There is evidence for abnormal C-fiber activity after nerve injury. For example, unaxotomized C nociceptors develop spontaneous activity after injury of adjacent nerves in a spinal nerve ligation model of the monkey (Ali et al. 1999) and after selective injury to myelinated neighboring fibers (Wu et al. 2001). It has been suggested that C-fiber activation is not necessary for the maintenance of mechanical allodynia after spinal nerve ligation in the rat (Liu et al. 2000) and that C-fiber somata in the DRG of this proximal nerve injury exhibit fewer changes in membrane properties and excitability than those of A and A fiber somata (Ma et al. 2003). In contrast, the more extensive changes observed in unaxotomized small-diameter neurons in the current study raise the possibility that C fibers may play a more important role in generating and/or maintaining mechanical allodynia after distal peripheral nerve injury. Clearly, mechanical allodynia after peripheral nerve injury requires activation of peripheral large-diameter fibers (Campbell et al. 1988), and medium- and large-diameter unaxotomized DRG neurons innervating the site of sensory testing also exhibited increased excitability after nerve injury in the current study.
Effect of perineural clonidine on injured and unaxotomized sensory afferents
Both anecdotal observations in patients with peripheral neuropathic pain and systematic studies in a rodent model of neuropathic pain demonstrate relief of pain and hypersensitivity after perineural injection of clonidine, resulting from actions on 2-adrenoceptors (Lavand'homme et al. 2002). The slow onset and prolonged duration of reduced hypersensitivity after perineural clonidine in nerve-injured animals (Lavand'homme et al. 2002) suggest the possibility of a temporary reversion of the altered phenotype of sensory afferents. Nerve injury is known to produce phenotypic shifts in primary afferents neurons including ion channels, neuropeptides and their receptors, and synaptic vesicle proteins (Xiao et al. 2002), which are thought to result in enhanced excitability. Perineural, but not intramuscular clonidine treatment partially or completely reversed each of the membrane properties that differed between PSNL and sham treatment, and this reversal extended across neurons of all sizes and in axotomized as well as unaxotomized neurons. Similar reductions in the proportion of neurons with abnormal membrane oscillation by clonidine after PSNL suggests that spontaneous activity could be reduced by this treatment, although the current study lacked adequate power to directly test this. We recognize that changes in physiologic properties at the cell soma do not necessarily reflect changes that may occur at peripheral nerve terminals (Shim et al. 2005). Because peripheral nerve blockade reduces ongoing pain as well as allodynia in patients with neuropathic pain (Gracely et al. 1992), reduction in spontaneous activity by perineural clonidine would be expected to reduce ongoing pain. This could not be tested in the current study, given the lack of a validated measure for ongoing pain in this rodent nerve injury preparation.
The mechanisms by which clonidine reversed hyperexcitability after PSNL were not tested in the current study. A direct effect of clonidine on neural activity is unlikely because clonidine affects axonal conduction only at much higher concentrations than those of the current study, is not reversed by 2-adrenoceptor antagonists, and lasts for only a few hours (Gaumann et al. 1994; Leem et al. 2000), rather than the slow onset and prolonged duration observed in the current study. We speculate that perineural clonidine reduces primary afferent excitability across neuron size and injury state by reducing a global signal for alterations in primary afferent phenotype leading to increased excitability, and that proinflammatory cytokines represent this signal. Peripheral nerve injury results in acute release of TNF from injured Schwann cells, followed by recruitment of macrophages that respond with a second wave of TNF release (Shubayev and Myers 2000). TNF is known to enhance excitability in primary afferent fibers (Sorkin et al. 1997) and their cell bodies (Liu et al. 2002a) and contributes to the development of pain and hypersensitivity in animal models of local inflammation or peripheral neuropathy (Cunha et al. 1992; Sommer et al. 1998; Woolf et al. 1997). In addition to its acute effects on ion channel properties and excitability (Liu et al. 2002a; Sorkin et al. 1997; Zhang et al. 2002), TNF also, with a 24-h delay, alters calcium currents in cultured sympathetic (Soliven and Albert 1992) and hippocampal neurons (Furukawa and Mattson 1998). Other proinflammatory products may be important as well. For example, perineural injection of a cyclooxygenase inhibitor also reduces hypersensitivity after PSNL, suggesting a role for prostaglandins (Ma and Eisenach 2002). We therefore speculate that reduced excitability after perineural clonidine after PSNL in the current study likely reflects clonidine's action to reduce proinflammatory cytokine and prostaglandin production by immune and other resident cells.
In summary, PSNL increases excitability of all size neurons that have been axotomized as well as their unaxotomized neighbors, which innervate the distal testing site of mechanical hypersensitivity. Increased excitability of large-diameter unaxotomized neurons is consistent with behavioral hypersensitivity, and increased spontaneous activity in both axotomized and unaxotomized neurons could play a role in ongoing pain. Perineural clonidine, administered 3 days earlier, reduces both behavioral hypersensitivity and measures of primary afferent excitability globally across neuron size and injury state. We speculate that clonidine's effect on excitability likely reflects a reduction in a signal, perhaps TNF or prostaglandins, that drives changes in primary afferent phenotype after peripheral nerve injury. These studies provide a rationale for controlled clinical trials of perineural clonidine injection at sites of nerve injury in patients with neuropathic pain and for further investigation into the mechanisms by which clonidine reduces primary afferent excitability.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. C. Eisenach, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157 (E-mail: jim{at}eisenach.us)
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P < 0.05 compared with post-PSNL clonidine group value.
