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Anesth Analg 2002;94:968-974
© 2002 International Anesthesia Research Society

PAIN MEDICINE

Spinal and Peripheral µ Opioids and the Development of Secondary Tactile Allodynia After Thermal Injury

Natsuko Nozaki-Taguchi, MD, and Tony L. Yaksh, PhD

Department of Anesthesiology, University of California, San Diego

Address correspondence and reprint requests to T. L. Yaksh, PhD, Department of Anesthesiology, University of California–San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0818. Address e-mail to tyaksh{at}ucsd.edu


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Local thermal injury to the paw leads to an increased sensitivity to a noxious stimulus applied to the site (primary thermal hyperalgesia) and an increased sensitivity to tactile stimuli in skin sites adjacent to the primary injury (secondary tactile allodynia; 2°TA). We sought to define the peripheral and spinal actions of µ opioids in regulating 2°TA. First, a mild thermal injury was induced on one heel, producing 2°TA. This 2°TA was blocked by pretreatment, but not posttreatment, with a topical µ-opioid agonist, loperamide (1.7%–5%). Second, 2°TA was blocked by intrathecal morphine (0.1–10 µg) pre- and postinjury. 2°TA reappeared when systemic naloxone was given before, but not after, injury in intrathecal morphine-pretreated rats. Intrathecal remifentanil, a short-lasting µ-opioid agonist, infused periinjury (3 µg/min), did not block subsequent primary thermal hyperalgesia, but it produced a dose-dependent (0.3–3 µg/min) abolition of 2°TA. Local tissue injury leads to 2°TA by the activation of opiate-sensitive afferents and the initiation of a cascade that persists in the absence of that initiating injury-induced stimulus.

IMPLICATIONS: Sensitivity to touch observed in areas adjacent to injury is blocked by opioids applied before, but not after, injury. This suggests that injury-activated opioid-sensitive fibers are responsible for sensitization and reveals a cascade that is diminished by pretreatment but not posttreatment, providing a rationale for adequate analgesia before injury (surgery) has occurred.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
After focal cutaneous thermal injury in humans, two behavioral components of nociception are observed (1,2). At the injury site, activation of small, high-threshold sensory afferents by a noxious thermal stimulus induces an exaggerated pain response, e.g., primary thermal hyperalgesia (1°TH), whereas application of a normally innocuous tactile stimulus to the skin adjacent to the injury site evokes pain, e.g., secondary tactile allodynia (2°TA). These two components are also observed in a rat model (3).

Previous work shows that 1°TH induced by focal thermal injury of the caudal portion of the rat paw is blocked by local application of a µ-opioid agonist—loperamide (4). Accordingly, we hypothesized that if the injury-induced opioid-sensitive afferent traffic were responsible for the 2°TA, then the local µ opioid acting at the primary site would prevent the off-site allodynia. With regard to the spinal mechanisms, we showed that both pretreatment and posttreatment with intrathecal (IT) morphine block 1°TH.1 If the 2°TA depends on central facilitation evoked by small afferent input from the injury site, pretreatment with spinal opioids should prevent the 2°TA. In contrast, spinal opioids do not generally suppress response to low-threshold tactile input (5). However, if the allodynic state depends on the sensitized dorsal horn neurons, persistent small afferent input, or both, posttreatment with an IT µ opioid is hypothesized to reverse the injury-induced 2°TA. In addition, an ultra-short-acting µ opioid given during or after the injury period will elucidate the important time window for the initiation and maintenance of 2°TA. A preliminary report of some of these data was published as an abstract.1


   Methods
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 Abstract
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 Methods
Results
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 References
 
All experiments were performed under the protocol approved by the institutional Animal Care Committee, University of California–San Diego. Male Holtzman-Sprague-Dawley rats (275–350 g; Harlan Industries, Indianapolis, IN) were housed in cages with free access to food and water at all times.

For the studies involving the IT administration of drugs, rats were prepared with chronically implanted catheters. Lumbar IT catheters were implanted according to the modification of the method as previously described (6). Briefly, under halothane anesthesia (1%–2% oxygen/air), a polyethylene catheter (PE-10; 8.5 cm) was inserted through an incision in the atlantooccipital membrane and advanced caudally. Rats were given at least 5 days after surgery for recovery before any testing was performed. Exclusion criteria included the presence of any neurological sequelae and catheter occlusion.

To assess the hind paw withdrawal threshold for mechanical stimulus, von Frey filaments with logarithmic incremental stiffness (0.41, 0.70, 1.20, 2.00, 3.63, 5.50, 8.50, and 15.10 g) (Stoelting, Wood Dale, IL) were used, and 50% probability withdrawal thresholds were calculated (7). In brief, beginning with the 2.0-g probe, filaments were applied to the plantar surface of a hind paw for 6–8 s, in an ascending or descending order after a negative or positive withdrawal response, respectively. Six consecutive responses from the first change in the response were used to calculate the withdrawal threshold (in grams) according to the method of Dixon (8). The testing site for assessment of 2°TA is shown in Figure 1. Animals were allowed at least 30 min to acclimate in the testing cage with a wire-meshed bottom, after which time baseline thresholds were assessed. Rats with a baseline mechanical threshold <10 g were excluded from the study.



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  		Figure 1. Effect of peripheral loperamide pretreatment on secondary tactile allodynia after thermal injury. Results are expressed as median (horizontal line) with 25th and 75th percentiles (boxes) and 10th and 90th percentiles (vertical lines). A, B, Time courses of paw withdrawal threshold (g) of injured paws with topical vehicle or loperamide treatment. Loperamide was applied 30 min before the injury, and the injury was given at Time 0 (dashed line). C, Dose-dependent effect of loperamide pretreatment shown at 60 min postinjury (T = 60). The diagram shows the rat hind paw with the injury site and testing point shown in a shaded area and X, respectively. A, *P < 0.05 versus preinjury threshold by the Friedman and modified Dunnett’s tests. C, *P < 0.05 versus vehicle by the Jonckheere test and modified Dunnett’s test.

 
To assess the hind paw thermal nociceptive threshold, a device modeled after that described by Hargreaves et al. (9) was used (UARDG, La Jolla, CA) (10). In brief, rats were placed into individual plastic cages (9 x 22 x 25 cm) and placed on a glass plate maintained at 30°C. A focused radiant heat source was aimed on the injured portion of the plantar surface of the hind paw. The time interval between the application of the light and the hind paw withdrawal response was defined as paw withdrawal latency (PWL [s]). This method will measure an escape response in rats at lower temperatures, e.g., thermal allodynia. Because there is no established method for measuring TH in rats, we used this method of thermal allodynia measurement to infer the presence of TH. For baseline PWLs, the average latency of two testings was calculated. Rats with baseline PWL <7 s and >13 s were excluded from the study. For postinjury testing, each paw was tested once.

To induce a thermal injury under continuous 2% halothane (oxygen/air) anesthesia with a nose cone, one hind paw of a rat was placed on a 52°C ± 1°C surface for 45 s, with a 10-g sand pouch placed on the heel portion of the paw for constant pressure. After this exposure, rats displayed significant 1°TH and 2°TA (3,11).

The following drugs were used: loperamide (ADL2-1294B; 5% loperamide cream) and its vehicle cream (Adolor Corporation, Malvern, PA), morphine sulfate (molecular weight [MW] = 668.8; Mallinkrodt, St. Louis, MO), remifentanil hydrochloride provided as lyophilate (MW = 413; Glaxo, Research Triangle Park, NC), and naloxone hydrochloride (MW = 327.37; Du Pont Pharmaceuticals, Garden City, NY). Morphine and remifentanil were dissolved in 0.9% sterile preservative-free saline. IT drugs were prepared such that the dose was delivered in a volume of 10 µL followed by a 10-µL saline flush. Remifentanil was given by continuous infusion. The dose was chosen from a previous study (12), with an infusion rate of 1.0 µL/min. Naloxone was dissolved with saline in a concentration of 1 mg/mL.

Baseline mechanical thresholds or PWLs were assessed before any treatment. In all experiments, mechanical thresholds and PWLs of the injured paw were assessed every 30 min for 3 h after injury. Drugs were given either before or after thermal injury.

Loperamide or the vehicle, in a quantity of 100 mg, was applied on the plantar surface of the paw, either on the primary area (heel portion of the paw where erythema is observed) or on the secondary area (front half of the paw, including the tori and the testing point) (Fig. 2). The drug was applied to the paw under light anesthesia (1%–2% halothane) for 10 min. This prevented the rat from licking the paw. The drug dose, quantity, and application method followed our previous study (4). Rats were assigned to one of the following three experiments: 1) loperamide or vehicle was applied 30 min before the injury on the primary area; 2) loperamide was applied 1 min after the injury on either the primary or the secondary area of the injured paw; or 3) intraperitoneal (IP) naloxone (1 mg/kg) was given 5 min before the loperamide (5%) pretreatment.



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  		Figure 2. Effect of peripheral loperamide posttreatment on secondary tactile allodynia after thermal injury. A, C, Time courses of paw withdrawal threshold (g) of injured paws with topical loperamide treatment. Injury was induced at Time 0 (dashed line), 1 min after which vehicle or loperamide was applied on either the primary or the secondary area. B, Effect of each treatment compared at 60 min postinjury (T = 60). The picture of the paw shows the injury site (shaded area), the drug application area (primary and secondary area), and the testing point (X). Graph plots are described in Figure 1. A, C, *P < 0.05 versus preinjury threshold by the Friedman test and modified Dunnett’s test.

 
In the Pretreatment group, IT morphine (0.1–10 µg) was given 5 min before the injury. Thirty minutes after the injury, mechanical threshold was determined. To determine whether the blockade of the initial injury would be sufficient to block the induction of 2°TA, naloxone (1 mg/kg) was given IP after the 30-min measurement.

In the Posttreatment group, thermal injury was induced and mechanical threshold was assessed at 30 min postinjury. Rats with a threshold >10 g at this point were excluded from the study (<10%). Immediately after the testing, morphine (0.1–10 µg) was given IT.

In the Pretreatment group, drug infusion began 15 min before the injury. Because of the dead space of the IT catheter, a drug effect was observed 5–7 min after the start of the infusion. Drug infusion (remifentanil 0.3–3 µg/min) was continued during anesthesia and the induction of thermal injury, immediately after which infusion was terminated. Accordingly, this treatment was termed "periinjury infusion." In the Posttreatment group, infusion started 7 min after injury and was continued for 15 min.

The effect of periinjury remifentanil infusion was also assessed on 1°TH. Drug infusion was performed in the same manner as the Periinjury Infusion group described previously, and thermal nociceptive threshold was tested.

To compare the analgesic effect of drug treatments on mechanical withdrawal thresholds, nonparametric analyses were used. Results are presented as median values. For the loperamide study and remifentanil study, all testing points (baseline to 180 min) were analyzed for vehicle treatments. Because the lowest median was typically observed at 60 min after injury (T = 60), the dose dependency of the drug effect or its antagonism was analyzed at T = 60. For the IT morphine study, thresholds at 30 min after each treatment were analyzed. Thus, in the pretreatment study, thresholds at baseline, 30 min after IT morphine (T = 30), and 30 min after IP naloxone (T = 60) were analyzed. Similarly, in the Posttreatment group, thresholds at baseline, 30 min postinjury (T = 30), and 30 min after IT injection of morphine (T = 60) were analyzed. Friedman’s test and the Jonckheere test (13) were used where appropriate. Multiple comparisons to preinjury or vehicle values were performed with nonparametric multiple comparison tests (modified Dunnett’s test) (13). PWLs to thermal stimulus were compared by using two-way repeated analysis of variance followed by Dunnett’s test for multiple comparisons. Results are presented as mean ± SEM; P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
After thermal exposure, rats typically displayed mild erythema at the injury site. However, this treatment did not result in any evident tissue injury, such as blistering, during the next 24 h. Nine rats were excluded from the study for having preinjury mechanical thresholds <10 g (<10%).

The baseline mechanical threshold of 15.0 g (n = 5) of naive rats before injury decreased significantly after injury with vehicle pretreatment (P < 0.004; Fig. 1A). When loperamide (1.7%–5%) was applied before injury at the site of the injury, a significant dose-dependent blockade of the 2°TA was observed (P < 0.002; Fig. 1, B and C). In contrast to the pretreatment, posttreatment with 5% loperamide applied to either the primary or the secondary area showed no blockade of the threshold decrease otherwise observed after injury (Fig. 2).

When naloxone (1 mg/kg) IP was given before the loperamide (5%) pretreatment, significant 2°TA was observed (P < 0.006). The threshold at T = 60 for the 5% Loperamide Treatment group and IP naloxone with 5% Loperamide group was 15 and 4.33 g, respectively (P < 0.006), showing a significant reversal of the antiallodynic effect of preinjury loperamide treatment by naloxone (1 mg/kg) IP.

The baseline tactile threshold of 15.0 g (n = 5) decreased significantly to 3.33 g at 30 min postinjury in rats receiving IT saline pretreatment (P < 0.03; Fig. 3A). Preinjury treatment with IT morphine produced a dose-dependent (0.1–10 µg) prevention of injury-evoked 2°TA (P < 0.0001; Fig. 3C).



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  		Figure 3. Effect of intrathecal (IT) morphine pretreatment on secondary tactile allodynia after thermal injury. Graph plots are described in Figure 1. Paw withdrawal threshold (g) time courses of the injured paw with IT saline and morphine 10 µg pretreatment are shown in A and B, respectively. IT drug was given 5 min before (arrow) the injury (dashed line, Time 0). After the measurement of thresholds at 30 min postinjury, naloxone (Nal; 1 mg/kg) was given intraperitoneally (IP). C, Dose-dependent effect of IT morphine pretreatment shown at 30 min after injury (T = 30). D, Withdrawal thresholds at 60 min postinjury (T = 60), showing no reversal of the morphine effect with IP naloxone. A, *P < 0.05 versus preinjury threshold by the Friedman test and modified Dunnett’s test. C, D, *P < 0.05 versus saline (Sal) by the Jonckheere test and modified Dunnett’s test.

 
In animals given naloxone (1 mg/kg IP) 30 min before IT morphine (10 µg) preinjury, no blockade of the 2°TA was observed (data not shown). In contrast, naloxone (1 mg/kg IP) given 30 min postinjury did not reverse the IT morphine blockade of the 2°TA otherwise produced by IT morphine given preinjury (P < 0.002; Fig. 3D). After the significant decrease of threshold from 15 to 4.88 g (n = 20; P < 0.0001), IT morphine, given at this time dose-dependently, reversed the 2°TA (P < 0.0001; Fig. 4A–C).



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  		Figure 4. Effect of intrathecal (IT) morphine posttreatment on secondary tactile allodynia after thermal injury. The plots are described in Figure 1. A, B, Paw withdrawal threshold (g) time courses of injured paws with IT morphine (0.1, 10 µg) posttreatment are shown. Injury was induced at Time 0 (dashed line), and thresholds were measured at 30 min postinjury, immediately after which IT morphine was given (arrow). C, Withdrawal at 60 min postinjury (T = 60) summarizes the dose-dependent effect. D, *P < 0.05 versus saline by the Jonckheere test and modified Dunnett’s test.

 
As shown in the previous experiment, IT morphine given before injury blocked the development of 2°TA, and this effect was not reversed by naloxone IP postinjury. This suggests the presence of a discrete time window in which spinal opioid receptor activation prevents the initiation of the 2°TA. To confirm this time window, we examined the effects of infusion of IT remifentanil periinjury and postinjury on the development of 2°TA. Continuous IT infusion of remifentanil periinjury prevented, in a dose-dependent (0.3–3 µg/min) fashion, the subsequent appearance of 2°TA (P < 0.001; Fig. 5A–C).



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  		Figure 5. Effect of intrathecal remifentanil infusion on secondary tactile allodynia after thermal injury. A, B, Time courses of paw withdrawal threshold (g) of injured paws with intrathecal vehicle or remifentanil (3 µg/min) infusion for 15 min given periinjury are shown. Injury was given at Time 0 (dashed line). Drug infusion (shaded box) was given 15 min before to 1 min after the injury. C, Dose-dependent effect of remifentanil infusion periinjury shown at 60 min postinjury (T = 60). D, Effect of drug infusion for 15 min postinjury (7–22 min postinjury) summarized by the effect observed at 60 min postinjury. Graph plots are described in Figure 1. A, *P < 0.05 versus preinjury threshold by the Friedman test and modified Dunnett’s test. C, *P < 0.05 versus vehicle by the Jonckheere test and modified Dunnett’s test.

 
In contrast to the periinjury treatment, remifentanil infusion (3 µg/min) for the same duration (approximately 15 min), but after the injury, showed no effect on the subsequent development of 2°TA (Fig. 5D). Treatment with IT remifentanil infusion 3 µg/min, only during the periinjury period, showed no effect on the subsequent development of 1°TH (treatment, P > 0.8; time, P < 0.0001; Fig. 6).



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  		Figure 6. Effect of intrathecal remifentanil infusion periinjury on primary thermal hyperalgesia. Paw withdrawal latency (PWL [s]) time course with intrathecal remifentanil infusion given periinjury is shown. Injury was given at Time 0 (dashed line), and the drug was given -15 to +1 min of the injury (shaded box). Periinjury remifentanil infusion did not block the subsequent primary thermal hyperalgesia. All points represent mean ± SEM. **P < 0.01, *P < 0.05 versus preinjury values by analysis of variance and Dunnett’s test.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
A local mild injury resulting in a mild erythema is accompanied by an increased sensitivity to a thermal stimulus applied to the injury site and to a tactile stimulus applied on the noninjured area. In humans, local activation of cutaneous C fibers (intradermal capsaicin) (2,14) or a local thermal injury (1,15) also evokes 1°TH and 2°TA. Thus, the behavioral analysis indicates that both 1°TH and 2°TA constitute psychophysical components of the pain state induced by an acute tissue injury.

Previous work has shown an increase in spontaneous discharge in small high-threshold afferents after tissue injury. Local µ opioids will block this spontaneous activity (16,17). Consistent with these findings, 1°TH after thermal injury was dose-dependently blocked by both pre- and posttreatment with peripheral loperamide (4). However, 2°TA was blocked by pre- but not posttreatment with topical loperamide at the injury site. Additionally, no effect was observed with loperamide on the 2°TA area, emphasizing the different mechanisms in play at the peripheral terminal for 1°TH and 2°TA. The complete reversal of the effect of pretreatment loperamide with naloxone IP indicates that the antiallodynic effect is mediated through opioid receptors. Accordingly, we believe that after acute tissue injury, peripheral input from small opioid-sensitive afferents is involved in initiating both 1°TH and 2°TA and in sustaining 1°TH and that input from the noninjured site is not regulated by local opioid receptors.

Our previous study (5) and these results show that both 1°TH and 2°TA after mild thermal injury are blocked by posttreatment with IT morphine. Further, pretreatment with IT morphine followed by pharmacological reversal with naloxone after injury prevented the subsequent display of 2°TA. This blockade of 2°TA with µ-opioid action during the periinjury period is substantiated by the results of the remifentanil study. Continuous IT infusion of 3 µg · µL-1 · min-1 of remifentanil completely blocks the thermal escape response in normal paws, with a recovery time of <10 minutes after the termination of infusion (12). As such, our data show that treatment during the induction of the injury was necessary and sufficient to block the subsequent 2°TA. This blockade may have resulted from the reduction of postinjury afferent input from the peripheral injury. However, this is not likely, because the same pretreatment with remifentanil did not block the development of subsequent 1°TH. This result and the results from the loperamide study suggest that a barrage of afferent opioid-sensitive input arising from an acute tissue injury initiates a change in spinal processing and that this change is maintained for a discrete interval, independent of the continuing input from the periphery. The sensitized spinal neurons are also sensitive to spinally-administered µ opioids. Conversely, this result implies a major role of peripheral sensitization for the development of 1°TH.

2°TA is believed to be mediated by low-threshold mechanoreceptors, as opposed to 1°TH, which is mediated by high-threshold afferents that have been sensitized by the injury milieu (18). One important difference emphasized by this study and others (19) is the relative sensitivity of the mechanical allodynia in the posttissue-injury model to spinal morphine, as contrasted to the insensitivity observed in the Chung neuropathy model (20). Opioids can bind presynaptically, as well as postsynaptically, to the primary afferents (21,22). This joint action is believed to account for the potent effect of spinal opioids on dorsal horn processing evoked by small afferent input (22), such as the effect on 1°TH. In contrast, spinal µ agonists have only a modest effect on large afferent-evoked activity (5). Accordingly, it is predicted to have only a modest effect on the behavioral effects observed in models in which small afferents do not play a role, such as the nerve injury-associated allodynia, as in the Chung neuropathy model. The observation that the injury-evoked allodynia is blocked by spinal opioids raises the possibility that the spinal opioid effect is postsynaptic and that the mechanisms of enhanced responsiveness (e.g., partial depolarization, phosphorylation of channels or receptors) are attenuated by the opioid-induced hyperpolarization.

Tissue injury-induced input serves to sensitize not only nerve endings at the injury site, resulting in 1°TH, but also the spinal system, so as to facilitate the large afferent input from noninjured tissue surrounding the injured tissue. The presence of this afferent-triggered central sensitization has led to controversial hypotheses regarding "preemptive analgesia," e.g., wherein prevention of an acute small afferent barrage may attenuate the subsequent pain state (23,24). These observations indicate that periinjury spinal opioids will prevent the subsequent manifestation of 2°TA, but not 1°TH. The importance of preemptive analgesia is reenforced, as is the importance of continued analgesic use in the treatment of 1°TH and established 2°TA.

Finally, our data in this model suggest the presence of a discrete time window in which the firing of afferent nociceptors is responsible for the induction of 2°TA. The simplicity of the animal model (e.g., a focal injury leading to a discrete and transient activation of primary afferents) permits us to discriminate between the mechanisms of 1°TH and 2°TA. Such simplicity does not always occur in the clinical situation. Continuing inflammation will also induce considerable firing and will continue to evoke secondary phenomena. Accordingly, continued analgesia to treat continuing afferent input as well as to prevent the development of hyperalgesia is necessary.


   Acknowledgments
 
Supported by National Institutes of Health Grant DA02110 (TLY) and, in part, by Chiba University (NN-T).


   Footnotes
 
1 Nozaki-Taguchi N, Jun J, Yaksh TL. Characteristics of primary and secondary hyperalgesia after thermal injury in rats [abstract]. Neuroscience 1998;351:2. Back


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 11, 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