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Anesth Analg 2002;95:979-984
© 2002 International Anesthesia Research Society

PAIN MEDICINE

Hyperalgesia During Opioid Abstinence: Mediation by Glutamate and Substance P

Xiangqi Li, MD, and J. David Clark, MD PhD

Veterans Affairs Palo Alto Health Care System and Stanford University Department of Anesthesiology, Palo Alto, California

Address correspondence and reprint requests to J. David Clark, MD, PhD, Veterans Affairs Palo Alto Health Care System, Anesthesiology, 112A, 3801 Miranda Ave., Palo Alto, CA 94304. Address e-mail to djclark{at}stanford.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Opioid-abstinence hyperalgesia (OAH) is a phenomenon characterized by thermal and mechanical hyperalgesia that occurs between intermittent doses of opioids or after the chronic administration of these drugs when administration is abruptly stopped. In these studies we attempted to determine whether the activation of spinal cord dorsal horn neurons was greater in mice with OAH than in control mice in response to the intrathecal administration of the primary neurotransmitters glutamate and substance P. After mice were treated with an established protocol consisting of the implantation of morphine pellets followed by removal after 6 days, the mice were hyperalgesic as assessed with the hotplate and Hargreaves thermal paw withdrawal assays. Mechanical allodynia was also demonstrated. The intrathecal injection of either glutamate (5–25 µg) or substance P (0.02–0.1 nmol) caused greater pain behaviors in mice with OAH than in control mice. Likewise, it was observed that the dorsal horn regions of OAH mice had more Fos-positive nuclei after either glutamate or substance P administration than did control mice. We conclude that mice with OAH exhibit increased pain behaviors and have increased numbers of Fos-positive nuclei in response to intrathecal glutamate and substance P administration when compared with control mice. Thus, spinal sensitization to primary neurotransmitters may be responsible in part for the manifestation of OAH.

IMPLICATIONS: Opioids are a mainstay of treatment for many types of chronic pain. These studies provide evidence that the hyperalgesia induced by chronic opioid administration may be in part to spinal neuroplastic changes.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Opioid-abstinence hyperalgesia (OAH) is a phenomenon characterized by thermal and mechanical hyperalgesia that can be observed between doses of intermittently administered opioids or after the cessation of administration of continuously administered opioids. After the induction of OAH, animals also exhibit increased pain behaviors in the formalin model of inflammatory pain and the incisional model of postoperative pain (1,2). Both systemic (1–5) and intrathecal (5–8) administration of opioids has been linked to OAH, suggesting a role for the spinal cord in the etiology of this phenomenon. Limited pharmacological information is available at this point, which suggests that µ-opioid receptors are involved in the induction of OAH, as are N-methyl-D-aspartate (NMDA) receptors (1,3). Once established, OAH can be reduced by the administration of several drugs, including nitric oxide synthase and heme oxygenase inhibitors, as well as NMDA receptor antagonists (1). This phenomenon is not limited to rodent models, because similar hyperalgesia has been documented in humans receiving systemic or intrathecal opioids for therapeutic purposes (9–13).

In addition to the experiments documenting the induction of OAH after the administration of intrathecal opioids, other evidence points to the spinal cord as playing some role in OAH. For example, Vanderah et al. (5) have shown that tonic descending spinal cord facilitation from the rostral ventromedial medulla during chronic exposure to opioids may be, at least in part, responsible for the etiology of OAH. Likewise, after chronic exposure to opioids, noxious stimulation of a rat’s hind paw with formalin leads to increased expression of spinal cord dorsal horn Fos in opioid-treated compared with control animals (14). The nuclear expression of Fos is often used as an index of spinal cord neuron activation after noxious stimulation. These data were interpreted to indicate that opioid receptor-expressing neurons in the spinal cord—especially in the superficial dorsal horn cells, where a great deal of sensory processing takes place—become sensitized to noxious input.

This series of studies attempts to extend our understanding of the role of spinal sensitization in OAH. The first hypothesis tested was that mice with OAH would manifest increased pain behavior in response to the intrathecal application of glutamate and substance P, substances involved in nociceptive signal transduction within the spinal cord. Morphine reduces the nociceptive behaviors and hyperalgesia caused by the intrathecal application of substance P and glutamate receptor agonists (15–17). Thus, the suggestion has been made that the substance P/glutamate receptor systems interact with opioid receptor systems at the level of the spinal cord dorsal horn. The second hypothesis was that Fos expression in superficial dorsal horn neurons would be induced to a greater extent in the spinal cords of the OAH mice than in control mice in response to intrathecal application of nociceptive neurotransmitters.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All experimental protocols were reviewed and approved by the Veterans Affairs Palo Alto Health Care System Subcommittee for Animal Studies before the initiation of work. All protocols conform to the guidelines for the study of pain in awake animals as established by the International Association for the Study of Pain. Every effort was made to minimize animal suffering and to use only the number of animals necessary to produce reliable scientific data. The mouse strain used for these experiments was the C57BL/6J line (Charles River, Hollister, CA). Male mice from 16 to 22 wk old (weight, 23–27 g) were used. All animals were kept six to eight to a cage with a 12:12-h light/dark cycle and food and water ad libitum. Groups of six to eight mice were used in the behavioral paradigms.

Generating mice with OAH was accomplished according to our recently described method (1). For these experiments, a 75-mg morphine pellet (NIDA) was first coated on one surface with acrylic nail polish, which prevented the disintegration of the tablet with time in the moist subcutaneous environment. Mice to be rendered hyperalgesic (OAH group) were briefly anesthetized with isoflurane, and a small subcutaneous skin pocket was made on the animal’s back into which a morphine tablet was placed, uncoated side down, followed by closure with surgical staples. Animals in the control group had a skin pocket made and had their incisions closed. Intermittent morphine abstinence for animals in the OAH group was accomplished by injecting naloxone 1 mg/kg subcutaneously on Days 2, 4, and 6 after pellet implantation. Control animals received saline at these times. On Day 6, morphine pellets were removed from animals in the OAH group. Control animals underwent reopening followed by reclosure of the skin pocket on Day 6. Behavioral and biochemical testing were performed beginning 18 h after the removal of pellets. Thus, the majority of studies presented here used two groups of mice: one group of control animals and another group with 18 h of abstinence from morphine.

Substances involved in nociceptive neurotransmission were injected intrathecally into mice according to the method of Hylden and Wilcox (18). For these injections, a small patch of fur over the lumbar area of the mice was shaved the day before experimentation. To assess nociceptive responses, mice were briefly restrained with a gloved hand, and a 30-gauge, 1/2-in. needle was inserted intrathecally at approximately the L5-6 level; appropriate positioning was signaled by advancement of the needle after walking the tip off the adjacent lamina and, often, by a brief twitch of the tail. Then, 5 µL of drug solution was injected with a 25-µL microsyringe (Hamilton, Las Vegas, NV). A preliminary series of experiments using motor block with 5% lidocaine as a test of appropriate intrathecal injection documented a success rate of approximately 95%. Mice were then placed on a glass surface in a clear plastic cylinder with a 20-cm diameter for observation of behaviors. The substance P and sodium glutamate used for these experiments were purchased from Sigma (St. Louis, MO). These were made in 0.9% saline with the pH titrated to 7.0–7.4 before the injections.

The hotplate assay was performed as previously described (19). Equipment for this assay was obtained from IITC (Woodland Hills, CA). The hotplate was set thermostatically at 52°C ± 0.1°C. Mice were placed in a square clear enclosure on the hotplate, and the time to licking of a hind paw, the end point of the assay, was measured with a stopwatch. Animals were left on the hotplate no longer than 60 s to prevent permanent tissue damage.

Mechanical allodynia was assayed with nylon von Frey filaments according to the algorithm described by Chaplan et al. (20), as we have used previously (1). In these experiments, mice were placed on mesh platforms in plastic enclosures. After 20 min of acclimation, fibers of sequentially increasing stiffness (n = 7; 0.2–2 g) were applied to the center of the plantar surface of the hind paw just distal to the first set of foot pads and left in place for 5 s. Purposeful withdrawal of the hind paw from the fiber was scored as a response. When no response was obtained, the next stiffest fiber in the series was applied; if a response was obtained, a less stiff fiber was next applied. Testing proceeded in this manner until four fibers had been applied after the first one that caused a withdrawal response, allowing the estimation of the mechanical withdrawal threshold.

Response latencies to noxious thermal stimulation were measured with the method of Hargreaves et al. (21) as we have modified it for use with mice (1). In this assay, mice were placed on a glass platform (23.5°C–24.0°C) in a plastic enclosure as described previously. After 20 min of acclimation, a beam of focused light was directed toward the same area of the hind paw as described for the von Frey assay. The time to purposeful withdrawal of the foot from the beam of light was measured. A 20-s cutoff was used to prevent tissue damage. The light beam intensity was adjusted to provide a 9- to 10-s baseline, thus facilitating the detection of thermal hyperalgesia. Two measurements were made per animal per test session.

Animals that undergo intrathecal injection of glutamate or substance P exhibit pain-related behavior characterized by licking, biting, and scratching the tail and hind limbs (22–24). For both of these substances, the majority of pain-related behavior occurs within the first 10 min after intrathecal injection. Thus, after animals were injected, they were observed for this pain-related behavior for the first 10 min after injection while the amount of time spent on the behavior was measured with a stopwatch.

Studies performed to quantify Fos expression in lumbar spinal cord tissue were performed as recently described (25,26). Briefly, animals were asphyxiated with CO2 60 min after intrathecal injection and then subjected to intracardiac perfusion with 10 mL of 0.9% NaCl. This was followed by perfusion with 20 mL of 4% paraformaldehyde in 0.1 M phosphate-buffered saline. The spinal cord was then extruded onto a chilled surface and carefully transected in the upper sacral and lower thoracic regions. This segment of tissue was postfixed for 4 h in paraformaldehyde, followed by incubation overnight in 30% sucrose at 4°C. After embedding in freezing medium, 40-µm sections were made at -20°C by using a refrigerated microtome (Leica, Germany) in a caudal to proximal manner. Sections were collected in groups of 12, which represented approximately 0.5 mm of spinal cord tissue as measured along the spinal cord’s longitudinal axis. Two to three sections of each group were subjected to toluidine blue staining to determine the spinal cord level to which they corresponded (25).

Sections corresponding to the L4 and L5 levels were processed for visualization of nuclear Fos expression by using a floating technique (26). Briefly, blocking took place overnight at 4°C with 5% dry milk, followed by overnight exposure to the primary antibody anti-Fos 1:10,000 (Santa Cruz Biotechnology, Santa Cruz, CA). After rinsing, avidin-biotin-complex reagents (Vector Laboratories, Burlingame, CA) were used to visualize immunoreactive structures. Examination of slides was performed with standard light microscopy by using an Olympus (Tokyo, Japan) BH-2 microscope coupled to a digital camera. Later, images were digitally overlaid with templates for the various spinal cord laminae (Photoshop software; Adobe, San Jose, CA), and Fos-positive nuclei were counted. Tabulation of Fos expression was performed by an investigator other than the person who collected the images. The images were digitally magnified when necessary to allow resolution of closely apposed nuclear profiles in the superficial dorsal horn. This procedure was performed for five sections per animal, and at least four animals were used for each experimental condition.

Statistical analysis of possible differences in pain behaviors or Fos expression was performed with Student’s t-tests. Our cutoff for significance was P < 0.05 or P < 0.01. Data are presented as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
To confirm that the mice used in this study did in fact become hyperalgesic after pretreatment, we measured hotplate licking latencies, paw-withdrawal latencies, and mechanical withdrawal thresholds of morphine/naloxone-treated mice (OAH mice) and controls. For OAH mice, hotplate licking latency was decreased from 23.0 to 13.2 s, thermal paw-withdrawal latency was decreased from 8.4 to 4.8 s, and mechanical von Frey withdrawal thresholds were decreased from 1.18 to 0.40 g. All of these changes were significant at the P < 0.01 level. Overt opioid withdrawal (wet-dog shakes, jumping, teeth chattering, and so on) was not observed in the abstinent group at 18 h after morphine pellet removal.

To evaluate the hypothesis that animals with OAH would demonstrate increased pain behaviors in response to the intrathecal administration of specific substances known to be involved in spinal nociceptive neurotransmission, we measured spontaneous pain behaviors after the injection of glutamate and substance P (Fig. 1). In these experiments, animals injected with saline alone demonstrated very little pain behavior (<10 s) over the 10 min after injection. Both glutamate and substance P caused vigorous caudally directed licking, biting, and scratching in a dose-dependent manner. In OAH mice, we observed increased licking behaviors in response to glutamate (Fig. 1A) or substance P (Fig. 1B).



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  		Figure 1. Both intrathecal glutamate and substance P elicit spontaneous nociceptive behaviors in mice. Various doses of these compounds were injected into either control (Cont.) or hyperalgesic (opioid-abstinence hyperalgesia; OAH) mice. A, Results with glutamate; B, results with substance P. At each dose of both compounds tested, OAH mice exhibited a greater duration of licking behavior as compared with controls; n = 6–8 per group; *P < 0.05; **P < 0.01.

 
To evaluate the hypothesis that animals with OAH would exhibit spinal Fos levels in excess of the Fos expression measured in control animals after the intrathecal injection of glutamate or substance P, we measured spinal Fos expression. Sample images from spinal cord sections as visualized with light microscopy are presented in Figure 2. Very little Fos was observed in spinal cord tissue after the injection of saline, several Fos-positive nuclei per slice were visualized after the injection of 0.1 nmol of substance P, consistent with previous reports (27), and many Fos-positive nuclei were observed in mouse spinal cord tissue after the injection of 25 µg of glutamate. More than 85% of the induced Fos was found in laminae I and II. Thus, we focused on these areas for our quantitative analysis.



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  		Figure 2. Intrathecal injection of glutamate and substance P elicits Fos expression in spinal cord dorsal horn neuron nuclei. A and B, Images of representative sections from saline-injected animals examined under 4x (A) or 10x (B; dorsal horn area) magnification. C, Image from an animal injected with 25 µg of glutamate intrathecally; D, image from an animal injected with substance P 0.1 nmol intrathecally.

 
The number of Fos-positive nuclei in laminae I and II were tabulated for various experimental conditions, and these data are presented in Table 1. As can be seen, laminae I/II Fos expression was similar in control and opioid-abstinent mice after saline injection. However, Fos expression was increased after the injection of small doses of either glutamate or substance P in OAH animals to levels above those measured in control animals. For these studies, we chose to use a submaximal dose of either glutamate or substance P to accentuate any differences in Fos expression between control and morphine-treated animals.


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  		Table 1. Expression of Fos-Like Immunoreactivity in Spinal Cord Laminae I and II
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The hypotheses we set out to test were 1) that mice with OAH induced by an established protocol manifest increased pain behaviors in response to the intrathecal application of nociceptive neurotransmitters and 2) that spinal cord Fos expression induced by nociceptive neurotransmitters would be increased in animals with OAH. The results of experiments measuring pain-related behaviors after the intrathecal injection of glutamate or substance P showed that these behaviors were in fact significantly enhanced in OAH mice. The differences in pain-related behaviors were perhaps best demonstrated in control and OAH mice when small doses of glutamate were used (Fig. 1). Complementing these results were the results of the Fos studies. In those experiments spinal cord dorsal horn Fos expression was greatly enhanced after intrathecal substance P and glutamate injection. Thus, nociceptive signaling in sensory areas of the spinal cord may be enhanced in mice exhibiting OAH, providing a mechanistic basis for this type of hyperalgesia.

Other reports have suggested that the chronic exposure of rodents to opioids might lead to neuroplastic events in the spinal cord. For example, several articles document hyperalgesia to peripherally delivered noxious stimuli after the selective intrathecal administration of opioids (5–8). This altered sensitivity to noxious stimuli might involve the activation of NMDA receptors (3,6), which has led to the comparison of OAH to neuropathic pain (4). Also, Vanderah et al. (5) have reported on a series of experiments looking at the alteration of descending spinal cord pathways in rats treated chronically with morphine, suggesting that at least part of the apparent alteration of spinal cord nociceptive processing in OAH has to do with tonic descending facilitation from the rostral ventromedial medulla. Other investigators have demonstrated that morphine metabolites such as morphine-3-glucur-onide can cause mechanical allodynia when injected intrathecally (28). We did not attempt to quantify these metabolites in our study. Although not specifically limited to spinal cord neurons, the studies of Crain and Shen (29,30) have clearly documented opioid receptor-mediated excitatory phenomena and hyperalgesia in sensory neurons.

Our studies perhaps build most directly on that of Rohde et al. (14), who measured increases in spinal cord Fos expression after hind paw formalin administration in rats chronically treated with morphine. They believed that perhaps opioid receptor-expressing neurons within the spinal cord were in some way sensitized to noxious input from the periphery. Our studies extend the findings of Rohde et al. by demonstrating that at least two of the principal spinal cord nociceptive neurotransmitters, glutamate and substance P, do have an enhanced ability to cause pain behaviors and Fos expression in the setting of OAH.

Finally, it should be recognized that hyperalgesia caused by the chronic administration of opioids is a clinically important issue. Both thermal hyperalgesia and mechanical allodynia have been observed in humans in whom therapeutically administered opioids have been rapidly withdrawn (11–13). Patients maintained on once-daily administration of methadone show thermal hyperalgesia in the cold pressor test without other evidence of opioid withdrawal (9,10). Others have suggested that short courses of opioids given during anesthesia provide enough exposure that some degree of hyperalgesia develops in the postoperative period (31,32). Furthermore, as an analgesic class, opioids are second only to nonsteroidal antiinflammatory drugs in terms of the number of prescriptions written for the treatment of chronic pain (33). Thus, a very large number of patients are exposed to opioids, and the analgesic benefit they derive may be compromised by the emergence of hyperalgesia. Further investigation in this area may help to devise strategies for opioid administration that would tend to avoid OAH or perhaps to provide treatment strategies for OAH once it is established.


   References
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 Introduction
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 Results
 Discussion
 References
 

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Accepted for publication May 17, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press