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Anesth Analg 2001;92:1558-1562
© 2001 International Anesthesia Research Society

PAIN MEDICINE

{alpha}-1 and {alpha}-2 Adrenergic Antagonists Relieve Thermal Hyperalgesia in Experimental Mononeuropathy from Chronic Constriction Injury

Allen H. Hord, MD, Donald D. Denson, PhD, Barry Stowe, MD, and Robert M. Haygood, MD

Department of Anesthesiology, Division of Pain Medicine, Emory University School of Medicine, Atlanta, Georgia

Address correspondence and reprint requests to Allen H. Hord, MD, Department of Anesthesiology, Emory University School of Medicine, 1364 Clifton Rd. N.E., Atlanta, GA 30322. Address e-mail to allen_hord{at}emory.org

Abstract

Phentolamine, a nonspecific {alpha}1- and {alpha}2-adrenergic antagonist, relieves pain in patients with reflex sympathetic dystrophy. We sought to determine whether phentolamine, prazosin ({alpha}1 antagonist), or SKF86466 ({alpha}2 antagonist) relieve thermal hyperalgesia in rats with neuropathic pain. Four days after producing a chronic constriction injury (CCI), thermal hyperalgesia was tested by measuring paw withdrawal latency (PWL). After injection of phentolamine, prazosin, or SKF86466 each at doses of 1, 2, or 5 mg/kg, PWL tests were measured at 5 min and repeated at 15-min intervals for 1 h. Phentolamine, prazosin, and SKF86466 1, 2, and 5 mg/kg provided statistically significant analgesia in rats with CCI for at least 65 min. PWL did not return to baseline levels after 1 or 2 mg/kg of prazosin or SKF86466 but did so after 35 min after phentolamine 2 mg/kg. After 5 mg/kg, PWL returned to preoperative values between 5 and 50 min for phentolamine, at 35 and 65 min for prazosin, and at 50 min for SKF86466. We conclude that both {alpha}1 and {alpha}2 peripheral receptors of the sympathetic nervous system are involved in the thermal hyperalgesia caused by CCI and that thermal hyperalgesia can be reversed by both {alpha}1 and {alpha}2 antagonists in a dose-dependent manner.

Implications: Thermal hyperalgesia in the chronic constriction injury model of mononeuropathy is mediated by {alpha} receptors. Although {alpha}1 and mixed {alpha}1- and {alpha}2-receptor antagonists have been used in humans to treat reflex sympathetic dystrophy, drugs that are highly specific postjunctional {alpha}2 antagonists may also be useful in the treatment of sympathetically mediated pain.

Sympathetic blockade has long been recommended for diagnosis and treatment of reflex sympathetic dystrophy (RSD). Sympathetically maintained pain (SMP) is a common feature of the RSD syndrome. In addition to local anesthetic sympathetic (ganglion) blocks and IV regional administration of guanethidine or bretylium, phentolamine temporarily relieves pain in patients with SMP (1,2). Decreases in spontaneous and stimulus-evoked pain appear to parallel the administration of increasing doses of phentolamine (1). In addition, the degree of pain relief after phentolamine correlates extremely well with the relief obtained from local anesthetic sympathetic block or IV regional block with guanethidine. The use of phentolamine as a test for RSD has been questioned by Verdugo and Ochoa (3), who suggest that pain relief is caused by a placebo response. However, the patients tested by Verdugo and Ochoa were not selected on the basis of their previous response to sympathetic blocks. Although not all patients with neuropathic pain respond to phentolamine, the study does not specifically address a subset of patients with SMP. Despite the contradictory data, demonstration of the efficacy of phentolamine in humans has encouraged the treatment of SMP with {alpha}1-receptor antagonists, including prazosin [which was previously described by Abram and Lightfoot (4)] and terazosin (5).

Systemic administration of the {alpha}2 agonist clonidine relieves thermal hyperalgesia in Bennett and Xie’s (6) chronic constriction injury (CCI) model of neuropathic pain in rats (7). In humans, clonidine provides significant analgesia in patients with RSD (8). The effect of clonidine results from stimulation of prejunctional {alpha}2 receptors, especially in the central nervous system, which decreases sympathetic output and promotes spinally mediated analgesia. However, peripheral blood vessels contain postjunctional receptors of both {alpha}1 and {alpha}2 subtypes. Postjunctional {alpha}2 receptors mediate cold-induced vasoconstriction in human fingers (9). In addition, mechanical allodynia in rats with neuropathic pain is blocked by {alpha}2 antagonists (10).

In the CCI model, phentolamine stops abnormal C-fiber firing in rats with neuropathic pain (11). In addition, phentolamine partially reverses mechanical allodynia in an L5/L6 spinal nerve ligation model of neuropathic pain (12). Because phentolamine is a peripherally acting {alpha}1 and {alpha}2 antagonist, it is not known which receptor mediates these effects.

The purpose of this study was to determine whether a highly selective, postjunctional {alpha}2 antagonist (SKF86466) relieves neuropathic pain. Because sympathetic blockade in the CCI model relieves thermal hyperalgesia more than mechanical allodynia (13), we chose to use paw withdrawal latency (PWL) to a heat stimulus as a test of analgesia. After confirming that thermal hyperalgesia in the CCI model of mononeuropathy was responsive to phentolamine, we examined the effect of postjunctional {alpha}1 or {alpha}2 receptor antagonism on thermal hyperalgesia.

Methods

The study was approved by the Institutional Animal Care and Use Committee of Emory University. Male Sprague-Dawley rats (Harlan, Hsd:Sprague Dawley) weighing between 275 and 300 g were used. Rats were housed in clear plastic cages with solid floors and loose hardwood chip bedding and allowed free access to food and water. The animals were acclimated to the environment and to the paw withdrawal testing procedure on three occasions before surgery. After three testing periods on different days, the rats underwent surgery.

The rats were anesthetized with 40 mg/kg intraperitoneal pentobarbital. Subsequent doses of pentobarbital 2 to 4 mg/kg were administered as necessary to maintain adequate anesthetic depth. After an adequate depth of anesthesia was verified by lack of response to tail pinch, surgery was performed to place four loosely constricting 4-0 chromic sutures around the left sciatic nerve, as previously described by Bennett and Xie (6). Identical surgery was then performed on the opposite (right) side, except that the ligatures were not placed (sham surgery).

Four to five days after CCI, the rats underwent PWL testing to verify the existence of thermal hyperalgesia. Groups of rats were randomly assigned to drug and dose administered. The rats were then injected intraperitoneally with 1, 2, or 5 mg/kg of the mixed {alpha}1/{alpha}2 antagonist phentolamine (Regitine; Ciba-Geigy, Basel, Switzerland), the specific {alpha}1 antagonist prazosin (Sigma, St. Louis, MO), or the peripherally acting specific {alpha}2 antagonist SKF86466 (courtesy of Dr. Paul Hieble). After 5 min, the rats underwent PWL tests every 15 min for 1 h, so tests occurred at 5, 20, 35, 50, and 65 min.

The animals were placed in a Plexiglas cage with air holes on a glass testing table in which they could move freely (e.g., make postural adjustments), and they were left to acclimatize to the environment for 10 min. The device used for measurement of PWL (Ugo Basile, Milan, Italy) consists of a radiant heat source (high-intensity projector lamp bulb) located below the glass floor and projected through a round aperture. A photoelectric cell detects light reflected off the paw and turns off the lamp and electronic clock when withdrawal of the paw occurs. Five sets of tests were done a minute apart on each hind paw at each time of measurement. Preoperative values were taken as the mean of PWL testing on three successive days immediately before surgery. Only animals with significant thermal hyperalgesia, defined as PWL on the left side being at least 20% shorter than on the right (PWLL/PWLR < 0.8), were used for testing of {alpha}-adrenergic antagonists.

Data are presented as mean ± SEM unless otherwise specified. PWL values for the CCI limb are expressed as a percentage of the corresponding value for the sham limb ([PWLL/PWLR] x 100). Differences between preoperative and postoperative times were assessed by using a one-way analysis of variance for repeated measures followed by a post hoc Scheffé test for multiple comparisons. In all cases, P < 0.05 was required for rejection of the null hypothesis.

Results

Animals that underwent CCI all had signs of the development of the neuropathic pain syndrome within 2 days after surgery. The toes of the affected limb were held together with the foot everted. The limb was used for walking but with an obvious limp. At rest, the foot was not placed in contact with the floor as frequently as on the control side. After thermal stimulation, the affected limb was held away from the floor for a longer period of time than was the control side. Despite the mononeuropathy, animals continued to groom themselves normally and gain weight.

Phentolamine, prazosin, and SKF86466 1, 2, and 5 mg/kg provided statistically significant analgesia in rats with CCI for at least 65 min (Figs. 1–3) (P < 0.05 for all doses at all times vs Time 0). PWL did not return to preoperative control levels after 1 mg/kg of phentolamine (Fig. 1). A 2 mg/kg dose of phentolamine completely reversed hyperalgesia, returning PWL to preoperative values for up to 35 min (P < 0.05 for the preoperative value versus Times 5, 20, and 35), whereas a 5 mg/kg dose did so for 50 min (P < 0.05 for the preoperative value versus Times 5, 20, 35, and 50). PWL did not return to preoperative levels after 1 or 2 mg/kg of prazosin (Fig. 2) and SKF86466 (Fig. 3). The 5 mg/kg dose returned PWL to preoperative values at 35 and 65 min for prazosin and at 35, 50, and 65 min for SKF86466.



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  		Figure 1. Phentolamine attenuates the thermal hyperalgesia associated with chronic constriction injury (CCI). Paw withdrawal latencies (PWL) are plotted as a function of time and dose. All doses produced a rapid and significant reduction in the thermal hyperalgesia associated with CCI. However, all data points are significantly lower than the preoperative values except those marked with # or *. The 2 and 5 mg/kg doses produced complete reversal of hyperalgesia at the 5-, 20-, and 35-min time points after injection (#). Only the 5 mg/kg dose produced complete reversal of hyperalgesia, lasting 50 min (*). All data are mean ± SD for n = 12 animals per group.

 


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  		Figure 2. Prazosin attenuates the thermal hyperalgesia associated with chronic constriction injury (CCI). Paw withdrawal latencies (PWL) are plotted as a function of time and dose. All doses produced a rapid and significant reduction in the thermal hyperalgesia associated with CCI. However, all data points are significantly lower than the preoperative values except those marked with #. Only the 5 mg/kg doses produced complete reversal of thermal hyperalgesia associated with CCI and only at 35 and 65 min after injection. All data are mean ± SD for n = 12 animals per group.

 


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  		Figure 3. SKF86466 attenuates the thermal hyperalgesia associated with chronic constriction injury (CCI). Paw withdrawal latencies (PWL) are plotted as a function of time and dose. All doses produced a rapid and significant reduction in the thermal hyperalgesia associated with CCI. However, all data points are significantly lower than the preoperative values except those marked with #. Only the 5 mg/kg doses produced a significant reduction in the thermal hyperalgesia associated with CCI starting at 35 and lasting for at least 65 min after injection. All data are mean ± SD for n = 12 animals per group.

 
Discussion

Experimental models of neuropathic pain have also shown evidence of response to blockade or destruction of the sympathetic nervous system. Neil et al. (13) examined the effect of guanethidine on rats with mononeuropathy caused by CCI. Rats were given either saline or guanethidine (30 mg/kg) on four consecutive days, either five days before or 10 days after surgery. Rats continued to have mechanical allodynia with or without guanethidine. However, treatment of rats, whether before or after sciatic nerve lesion, prevented or successfully reversed heat and cold sensitization. This was confirmed by Perrot et al. (14), who gave guanethidine for seven days to rats with a CCI.

By using their model of L5 and L6 spinal nerve ligation, Kim et al. (12) produced thermal hyperalgesia, and mechanical allodynia was measured by withdrawal frequency to von Frey filaments. They performed surgical sympathectomy on the rats, either one week before or one, three, or five weeks after nerve root ligation. Mechanical allodynia and thermal hyperalgesia normalized in all groups after surgical sympathectomy, but not in a group of animals who had sham surgery. In contrast, mechanical allodynia was significantly decreased but not abolished by phentolamine 0.5 or 4 mg/kg or guanethidine 30 mg/kg. In this model, mechanical allodynia appears to be least effected by sympathectomy. In fact, Ringkamp et al. (15,16) have shown that neither surgical sympathectomy nor chemical sympathectomy with phentolamine, yohimbine, or prazosin relieve mechanical allodynia in the L5/L6 spinal nerve ligation model.

In the partial sciatic nerve transection model, treatment with guanethidine postoperatively relieved mechanical allodynia and thermal hyperalgesia (17). In contrast, preoperative sympathectomy relieved only thermal hyperalgesia.

Despite the evidence that sympathetic denervation prevents or reverses mechanical allodynia and thermal hyperalgesia, few studies have investigated the specific subtype of {alpha} adrenoreceptor involved in hyperalgesia after mononeuropathy. Although some authors have assumed that the {alpha}1 receptors are solely responsible for allodynia and hyperalgesia in patients with RSD (1,5), there is evidence in rats that mechanical allodynia after chloroform application to the hind paw is reversed by either the mixed {alpha}1/{alpha}2 phentolamine or the {alpha}2 antagonist yohimbine, but not by the {alpha}1 antagonist prazosin (18). Similarly, in a partial sciatic nerve transection model of neuropathic pain, local administration of phentolamine and yohimbine relieved hyperalgesia, whereas prazosin did not (19).

We used phentolamine as a mixed {alpha}1/{alpha}2 antagonist and compared it with prazosin, a highly selective {alpha}1 antagonist, and SKF86466, a highly selective {alpha}2 antagonist. Phentolamine has nearly equal affinity for {alpha}1 and {alpha}2 receptors, with an {alpha}1/{alpha}2 affinity ratio of 3:1 (20). Prazosin is so selective for {alpha}1 versus {alpha}2 receptors that it is used as a pharmacologic probe in conducting dissociation constant experiments on other {alpha}-adrenergic drugs (21). Its affinity for the {alpha}1 receptor is nearly 4000 times more than for the {alpha}2 receptor (22). SKF86466 has an {alpha}2 receptor affinity similar to rauwolscine and an {alpha}2/{alpha}1 affinity ratio of more than 10,000 (23). Although SKF86466 is a potent antihypertensive drug in rat models of hypertension, it produces no blood pressure changes in normotensive rats in doses up to two mg/kg when given IV (24). SKF86466 is safe in doses up to 40 mg/kg and has a duration of antihypertensive effect of six hours versus 90 minutes for phentolamine.

We have shown that antagonists of both {alpha}1 and {alpha}2 receptor subclasses relieve thermal hyperalgesia in the CCI model of neuropathic pain. The reason for the equal efficacy of both antagonists is unknown. It is unlikely that the doses administered in this investigation were large enough to produce nonselective effects. However, the relative contribution of each subclass of adrenergic receptors on sympathetic stimulation may change with time after CCI. A study by Moon et al. (25) indicates that {alpha}2 sensitivity develops after L5 and L6 nerve ligation only after surgical sympathectomy. The authors suggest that {alpha}2 receptor proliferation and rekindling by {alpha}2 agonists is a result of sympathetic denervation. However, in Bennett and Xie’s (6) mononeuropathy model, which was used in our study, Wakisaka et al. (26) have shown the disappearance of sympathetic innervation in the limb over the first 30 days after CCI. Therefore, one would expect a decrease in neurogenically mediated stimulation after CCI. Sympathetic stimulation probably occurs by activation of postjunctional receptors by circulating catecholamines, as suggested by previous authors (19,27). We would expect this increase in sensitivity of extrajunctional {alpha}2 receptors to norepinephrine to develop as sympathetic innervation disappears after CCI. Wakisaka et al. (26) showed a significant decrease in sympathetic vasoconstrictor innervation at five days after CCI. Therefore, it is possible that both {alpha}1 and {alpha}2 receptors are represented in the rat hind limb at four days after CCI, thus explaining the efficacy of both antagonists in our study. Our findings may have been different on the first postoperative day, when sympathetic innervation to the limb is still largely intact and extrajunctional receptors have not upregulated, or on postoperative Day 30, when sympathetic innervation to the limb is absent and {alpha}2 receptor upregulation has developed.

It is not surprising that {alpha}2 adrenoreceptors are involved in the neuropathic pain syndrome. Although there are prejunctional {alpha}2 receptors (especially in the central nervous system) that modulate sympathetic outflow, postjunctional {alpha}2 receptors in the periphery control arteriolar and venous blood flow. In addition, {alpha}2 receptors are responsible for the vascular response to norepinephrine (28,29). Sympathetically mediated vasoconstriction in the cutaneous vascular bed of the cat paw is more effectively blocked by the {alpha}2 antagonists yohimbine and phentolamine than by prazosin (30). In the same model, Karasawa and Koss (31) have shown that {alpha}1-receptor antagonists are more potent in increasing total limb blood flow, whereas {alpha}2 antagonists more effectively increase blood flow in the cutaneous bed. These authors also showed that a combination of {alpha}1 and {alpha}2 antagonists was more effective than either drug alone in increasing blood flow in both large vessels and the cutaneous vascular bed. We have previously shown that hind limb perfusion in the rat is markedly decreased after CCI (32). On the basis of our current results showing a behavioral response to both {alpha}1 and {alpha}2, we believe that the effect of {alpha}2 antagonists on perfusion after CCI should be investigated, because vasoconstriction may cause tissue injury, which facilitates neuropathic pain by the release of inflammatory mediators (33).

In summary, thermal hyperalgesia in the CCI model of mononeuropathy developed by Bennett and Xie (6) is mediated by {alpha} receptors. Although {alpha}1 and mixed {alpha}1/{alpha}2-receptor antagonists have been used in humans to treat RSD, drugs that are highly specific postjunctional {alpha}2 antagonists may also be useful in the treatment of sympathetically mediated pain.

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Accepted for publication January 19, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press