Anesth Analg 2004;98:420-426
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000096066.26157.2A
PAIN MEDICINE
The Antinociceptive Potencies and Interactions of Endogenous Ligands During Continuous Intrathecal Administration: Adenosine, Agmatine, and Endomorphin-1
Gabriella Kekesi*,
Ildiko Dobos*,
György Benedek, MD DSc*, and
Gyöngyi Horvath, MD PhD*,
*Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary; and
Department of Physical Therapy, Faculty of Health Science, University of Szeged, Szeged, Hungary
Address correspondence and reprint requests to Gyöngyi Horvath, MD, PhD, Department of Physiology, Faculty of Medicine, University of Szeged, PO Box 427, H-6701, Szeged, Hungary. Address e-mail to horvath{at}phys.szote.u-szeged.hu
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Abstract
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Recently, a series of endogenous ligands related to inhibition of sensory transduction of noxious stimuli at the spinal level has been described, including endomorphins, agmatine, and adenosine, which act on different receptors; however, little data exist concerning their effect during continuous administration or their interactions. In this study, we investigated the antinociceptive properties of continuously administered (for 60 min) adenosine and agmatine on carrageenan-induced thermal hyperalgesia by means of a thermal paw withdrawal test in awake rats. The possible interaction between endomorphin-1 and adenosine or agmatine was also determined. Continuous administration of adenosine (0.3–3 µg/min) did not influence the paw withdrawal latencies of the normal or inflamed paws during the infusion but in larger doses it resulted in a significant increase in latencies after the cessation of the infusion. Agmatine (0.3–3 µg/min) dose-dependently decreased the hyperalgesia, but the largest dose caused a temporary excitation in 50% of animals. The continuous administration of adenosine or agmatine (3 µg/min) potentiated and prolonged the antinociceptive effect of endomorphin-1 (1 µg/min). Our results revealed that adenosine and agmatine have a small antinociceptive efficacy during continuous intrathecal administration but that both potentiate the effect of endomorphin-1. These data suggest that the combination of these endogenous ligands might represent novel targets for the therapeutic modulation of pain; however, the systematic examination of side effects is essential.
IMPLICATIONS: Adenosine and agmatine have little antinociceptive efficacy during continuous intrathecal administration, as shown by the inflammatory pain test in rats, but both potentiate the effect of endomorphin-1. These data suggest that the combination of these endogenous ligands might represent novel targets for the therapeutic modulation of pain; however, the systematic examination of side effects is essential.
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Introduction
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One of the cardinal features of inflammatory states is hyperalgesia—an excessive response to noxious stimuli. One study (1) implicated a series of receptors, ion channels, and transmitters involved in inflammatory pain at different sites, including the spinal level. The mechanisms by which inflammatory mediators interact with neurons producing hypersensitivity were also explored (2). The detailed biochemical and cellular mechanisms underlying painful stimuli are being revealed as more molecules are cloned and as their functions are elucidated. A series of endogenous ligands related to inhibition of sensory transduction of noxious stimuli at the spinal level has also been described. These ligands include endomorphins acting on µ-opioid receptors; agmatine acting on 
2, imidazoline, and N-methyl-D-aspartate (NMDA) receptors; and adenosine acting on adenosine receptors (3,4). The application of the endogenous antinociceptive ligands may have a number of advantages, including fast elimination and low toxicity (5,6). Furthermore, the combinations of endogenous ligands might have different types of interactions than combinations of compounds that act on the same receptors, because their receptor affinity, selectivity, or both might differ from those of the synthetic drugs (3,7). However, little data are available on the interactions between different endogenous ligands on nociception (5).
The role of 2-adrenoceptors in antinociception and their ability to potentiate opioid-induced analgesia at the spinal level is well known from studies with clonidine (8). Although agmatine also binds both to imidazoline and 2-adrenoceptors, its profile of action is different (7). In contrast to clonidine, agmatine does not influence acute pain sensitivity but potentiates morphine-induced analgesia when given subcutaneously (9,10). Our earlier study showed that agmatine pretreatment, but not posttreatment, decreased inflammatory pain and that larger doses caused severe side effects (11). We postulated that continuous administration of smaller doses of agmatine would cause pain relief without side effects, and direct examination of this possibility was the first goal of this study.
Adenosine receptor stimulation produces analgesia by both peripheral and central mechanisms, and a variety of molecules are being developed, including direct agonists, allosteric modulators, and uptake or metabolism inhibitors, to provide analgesia through this non-opioid mechanism (4,12,13). Although several reports have suggested the antinociceptive effect of synthetic adenosine derivatives or adenosine kinase inhibitors in different pain tests (acute, inflammatory, and neuropathic pain models) (4,12), only a few laboratories (e.g., Alf Sollevi’s and James Eisenach’s) have investigated adenosine in rats or humans at the spinal level (14–22). Most of these studies observed effective antinociception in neuropathic pain states but no effect on normal pain sensitivity (20,22). Only one human study investigated allodynia after intrathecal (IT) adenosine administration by using a mustard oil model (14). Adenosine did not influence the level of hyperalgesia, but it decreased the area of tactile allodynia in neurogenic inflammation induced by mustard oil. A second goal of our study was to investigate the effect of continuous IT administration of adenosine in the carrageenan-induced inflammatory pain model.
In 1997, novel opioid tetrapeptides—endomorphin-1 and endomorphin-2—were isolated from bovine and human brain; these exhibit high affinity and selectivity for µ-opioid receptors (23). Several behavioral studies suggest that both peptides produce analgesia via µ-opioid receptors in acute, inflammatory, and neuropathic pain in rodents (3). These agents have a high potency, but low efficacy, short-lasting effects, and acute tolerance were also observed. We postulated that the combination of endomorphins with adenosine or agmatine might result in potentiated antinociception similar to morphine combinations (21,24). Therefore, the last goal was to investigate the antinociceptive effect of continuous IT coadministration of adenosine or agmatine with endomorphin-1.
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Methods
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The procedures involved in the animal surgery and nociceptive testing were approved by the Institutional Animal Care Committee of the Faculty of Medicine at the University of Szeged. An IT catheter (PE-10 tubing) was implanted for male Wistar rats (n = 142; weight, 260 ± 3.1 g) under ketamine/xylazine anesthesia [S(+)-ketamine, Pfizer Med-Inform; Rompun TS, Bayer AG, Leverkusen, Germany; 72 and 8 mg/kg intraperitoneally, respectively]. The tip was placed at the level between vertebrae T12 and L2 (25). The rats were allowed to recover for at least 4 days before testing. The animals were housed individually, with free access to food and water. Animals exhibiting a postoperative neurological deficiency were excluded from the study. During the experiments, the animals were randomly assigned to the treatment groups (n = 6–11 rats per group). The observers were blinded to the treatment administered. The antinociceptive effects of the applied substances on carrageenan-induced inflammation were assessed by using the paw withdrawal (PWD) test. The rats were placed on a glass surface in a plastic chamber and were allowed to acclimatize to their environment for at least 20 min before testing. The heat stimulus was then directed onto the plantar surface of each hindpaw. The baseline PWD latencies (precarrageenan baseline values at -180 min) were measured. The cutoff time was set at 20 s to avoid tissue damage. Unilateral inflammation was induced by intraplantar injection of 1.5 mg/0.1 mL of lambda carrageenan (Sigma-Aldrich Kft., Budapest, Hungary) into one of the hindpaws. PWD latencies were obtained again 3 h after carrageenan injection (postcarrageenan baseline values at 0 min) and then during and after the continuous IT drug administration at 10-min intervals for 130 min.
Adenosine (FW [formula weight] = 267.2), agmatine sulfate (agmatine; FW = 228.3), and endomorphin-1 (FW = 610.7) (Sigma-Aldrich Kft.) were administered alone or in combination (endomorphin-1 and adenosine or agmatine) in a continuous IT infusion. The duration of the infusion was 70 min. The total volume of the drugs was 60 µL, and this was flushed with an additional 10 µL of 0.9% NaCl at the end of the infusion. The flow rate was 1 µL/min. Drugs were freshly dissolved in physiological saline on the day of the experiment. Physiological saline was used as control in all series.
The first series of experiments was performed to determine the dose-response and time-course effects of adenosine (0.3, 1, or 3 µg/min), agmatine (0.3, 1, or 3 µg/min), and endomorphin-1 (0.1, 0.3, or 1 µg/min) alone. The second series of experiments was performed with a fixed dose ratio (1:3) of endomorphin-1 (0.1, 0.3, or 1 µg/min) and adenosine or agmatine (0.3, 1, or 3 µg/min) to determine the possible interaction of these endogenous substances on nociception.
Data are presented as means ± SEM. Data sets were examined by analyses of variance with repeated measures. The area under the curve (AUC) values were obtained by calculating the area during (10–60 min) and after (100–130 min) drug administration. These data sets were examined by one-way analysis of variance. The significance of differences between experimental and control values was calculated by using the Newman-Keuls post hoc test. A P value of <0.05 was considered significant.
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Results
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The baseline PWD latencies were similar for the ipsilateral and contralateral hindpaws (9.9 ± 0.13 s and 9.8 ± 0.14 s, respectively; n = 143). The intraplantar injection of carrageenan induced inflammation in the treated paw, as evidenced by edema and erythema. Three hours after carrageenan administration, the PWD latency reduced significantly, to 3.3 ± 0.09 s, and this persisted throughout the investigation in the vehicle-treated group. A small but significant increase in PWD latency was observed from 60 min, so statistical comparisons were made to the control group.
On the noninflamed side, the time-response curves showed a slight but not significant increase in the PWD latency during the administration of the largest dose of endomorphin-1 (Fig. 1A). On the inflamed side, endomorphin-1 caused a dose-dependent increase in the PWD latencies (Fig. 1B). The largest dose caused significant increases in the PWD latencies at all of the time points during the infusion. The cessation of administration resulted in a gradual decrease in the PWD latencies. Analysis of the AUC data revealed that hyperalgesia decreased during the administration of all doses, but this effect could not be observed after the infusion (100–130 min). Furthermore, the largest dose of endomorphin-1 also caused significant antinociception in the normal paw (Fig. 2).
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Figure 1. Curves indicating the time-response effects of (A and B) endomorphin-1 (EM-1); (C and D) adenosine (ADO), and (E and F) agmatine (AGM). The section between the arrows represents the duration of the microinfusion. Symbols denote P < 0.05 compared with the control group: x0.1 µg/min EM-1; +0.3 µg/min EM-1, ADO, and agmatine; *1 µg/min EM-1, ADO, and AGM; and #3 µg/min ADO and AGM. Values are means ± SEM of the data for 6–11 animals. PWD = paw withdrawal.
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Figure 2. The magnitudes of the dose-dependent effects of different doses of endomorphin-1 (EM-1), adenosine (ADO), and agmatine (AGM) alone during drug administration (10–60 min) (A and C) and after its termination (100–130 min) (B and D) on the noninflamed (A and B) and inflamed (C and D) paws are presented as area under the curve (AUC) values. *Significant (P < 0.05) difference between the data points and the results for the control (C) group.
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The time-response curves (Fig. 1, C and D) and the AUC analysis (Fig. 2) show that adenosine administration did not influence the PWD latency during the infusion, but in larger doses (1 or 3 µ/min) it caused significant increase in the PWD latency on both sides after the cessation of the infusion. There were no signs of motor impairment.
None of the administered doses of agmatine significantly changed the PWD latencies on the noninflamed side (Fig. 1E). Agmatine caused a dose-dependent increase in the PWD latencies on the inflamed side during and after the infusion (Fig. 1F). The largest dose caused significant increases in the PWD latencies at some time points compared with the control group. This suggests that the hyperalgesia was merely decreased, but not relieved. Analysis of the AUC data also revealed that the hyperalgesia decreased dose-dependently in the 10- to 60-min interval and that the cessation of administration resulted in a gradual decrease in the PWD latencies; however, the 3 µg/min dose caused a significant increase in that time also (Fig. 2). It should be mentioned that the largest dose caused a temporary excitation in 50% of animals, as manifested by excessive movement during the experiment.
Our preliminary experiments revealed that larger doses of all drugs (2 µg/min endomophin-1, 5 µg/min agmatine, and 10 µg/min adenosine; unpublished data) caused motor impairment or excitation (5,6); therefore, in the largest-dose combinations, we applied 1 µg/min of endomorphin-1 with 3 µg/min of agmatine or adenosine. The smaller doses of adenosine and endomorphin-1 did not cause any potentiated antinociception compared with the endomorphin-1-treated group (data not shown). The time-response curves showed that the largest dose of adenosine (3 µg/min) significantly increased the antinociceptive effect of endomorphin-1 (1 µg/min) during and after the infusion on the inflamed side (Fig. 3C). The AUC analysis showed significant increases on both sides during the infusion (Fig. 4, A and C). After the cessation of administration, the AUC values showed that adenosine increased the duration of the effect of endomorphin-1 only on the inflamed side (Fig. 4C). The combination treatment did not cause motor impairment.
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Figure 3. Curves indicating the time-response effects of the largest-dose combination of endomorphin-1 (EM-1) (1 µg/min) and adenosine (ADO) or agmatine (AGM) (3 µg/min) on the noninflamed (A and B) and on the inflamed (C and D) paws. The section between the arrows represents the duration of the microinfusion. +Significant difference (P < 0.05) between the results for the combination-treated and EM-1-treated group animals. Values are means ± SEM of the data for 6–10 animals. PWD = paw withdrawal.
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Figure 4. The antinociceptive effects of 1 µg/min endomorphin-1 (EM-1), 3 µg/min adenosine (ADO), and agmatine (AGM) alone and in combination during drug administration (10–60 min) and after its termination (100–130 min) on the noninflamed (A and B) and inflamed (C and D) paws are presented as area under the curve (AUC) values. +Significant (P < 0.05) difference between the EM-1- and combination-treated animals. Values are means ± SEM of the data for 6–10 animals.
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The smaller doses of agmatine and endomorphin-1 did not result in potentiated antinociception compared with the endomorphin-1-treated group (data are not shown). The time-response curves showed that the largest dose of agmatine (3 µg/min) plus endomorphin-1 (1 µg/min) caused a significant increase at 10 min compared with endomorphin-1 treatment on the noninflamed side (Fig. 3B). On the inflamed side, agmatine significantly potentiated the antihyperalgesic effect of endomorphin-1 during the infusion. The AUC analysis showed that the combination caused a potentiated effect on the inflamed side during and after the administration of the drugs compared with the endomorphin-1 treatment (Fig. 4D). However, the comparison of the agmatine plus endomorphin-1 combination with agmatine treatment alone showed significant differences during but not after the infusion. The largest dose caused a temporary excitation in 30% of animals.
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Discussion
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Although the combination of synthetic drugs acting at different receptors is a well established method for pain therapy, the administration of a combination of endogenous ligands is not common. Our recent results suggested that kynurenic acid (an endogenous NMDA receptor antagonist) has a significant influence on the antinociceptive effect of endomorphin-1 (6). The present data demonstrate that agmatine and adenosine have low efficacy alone on inflammation-induced thermal hyperalgesia during continuous IT administration. However, both drugs significantly potentiated and prolonged the antihyperalgesic effect of endomorphin-1. Furthermore, the largest dose (3 µg/min) of agmatine caused excitation, which could have interfered with the measurements.
A number of studies have shown that spinal administration of adenosine and adenosine analogs inhibits pain transmission or influences antinociception by morphine in different animal models (4,12). Adenosine receptors (A1 and A2) are localized primarily on neurons postsynaptic to primary afferents and descending projections within the dorsal horn, but some receptors are present on central terminals of primary afferent neurons (4). The action at the A1 receptor most likely accounts for inhibition of the postsynaptic actions of substance P and excitatory amino acids (26). The administration of adenosine analogs causes side effects such as motor weakness or autonomic changes (4); therefore, the nontoxic adenosine might be a possible drug for pain therapy (20). However, the single administration of IT adenosine does not seem to be an effective antinociceptive method (19). Originally DeLander and Wahl (26) showed that IT adenosine inhibited the substance P- and NMDA-induced behavior. Several studies were performed with adenosine administered IT in healthy volunteers and patients (14,15,17). It was observed that the IT adenosine injection of 1000 µg lacked side effects in healthy volunteers and that the compound attenuated different types of experimental pain (14). Eisenach et al. (19) and others (20–22) have performed both animal and human studies with endogenous adenosine at the spinal level. They demonstrated that the adenosine did not influence the acute pain sensitivity (allodynia) in either rats or humans (19,22). In the present experiments, it was surprising that the effect of adenosine was observed only after the cessation of the infusion, not during it, and that the effect tended to be biphasic; however, Eisenach et al. (19) and Bantel et al. (27) also found a long-lasting effect of adenosine. They suggested that the causes for the long-lasting pharmacodynamic effect of IT adenosine in neuropathic rats may include repletion of depleted adenosine stores in the spinal cord tissue itself; prolonged activation of A1 receptors, leading to decreased activity of adenosine kinase, thereby decreasing adenosine’s uptake; or transient blockade of the sensitization process, which could take several hours to recover (27).
There are several studies of morphine with adenosine at the spinal level (4). Within the spinal cord, a component of the antinociceptive action of morphine is due to the local release of adenosine. This was originally proposed on the basis of the ability of methylxanthines to inhibit spinal antinociception by morphine (28). Subsequently, morphine was shown to release adenosine from the spinal cord; thus, it was suggested that this mechanism mediates spinal analgesia by morphine (28,29). When coadministered spinally with opioid, both adenosine analogs and an adenosine kinase inhibitor produce an additive interaction with µ-opioids but a synergistic interaction in combination with 
- and 
-opioid receptors (24). Lavand’homme and Eisenach (21) also investigated the interaction of morphine with adenosine. Similarly to Sawynok et al. (29), they found that morphine normally stimulates the spinal release of adenosine; however, this effect of morphine is diminished in spinal nerve ligation animals (30). Furthermore, the antinociceptive effect of morphine was enhanced in an additive manner by spinal adenosine (21). We found that the coadministration of the two endogenous drugs (adenosine and endomorphin-1) acting at µ-opioid and adenosine receptors caused a potentiated antinociception during continuous IT administration. Because the IT administration of adenosine is not associated with neurotoxicity (18,20), the human application might offer a new possibility for pain therapy.
Agmatine is formed by the enzymatic decarboxylation of L-arginine (31) and binds with high affinity to 2-adrenergic and imidazoline receptors (32,33). In addition, agmatine antagonizes NMDA receptors (34) and inhibits nitric oxide synthase (35). All of these effects should moderate chronic pain accompanying inflammation at the spinal level (36). Our study (11) suggests that agmatine before treatment, but not post-treatment, decreased the carrageenan-induced thermal hyperalgesia, but Fairbanks et al. (36) observed that IT post-treatment agmatine decreased mechanical hyperalgesia. We suggest that the difference in results might be due to the different types of pain tests. There are some reports suggesting an advantageous interaction between agmatine and morphine. It has been shown that agmatine significantly potentiated the antihyperalgesic effect of morphine after IT administration (11). Furthermore, it significantly enhanced the antinociceptive effect of morphine administered systemically, intracerebroventricularly, or IT in the tail-flick test in mice (9,37). However, Fairbanks and Wilcox (10) did not observe potentiated analgesia in the acute heat pain test in mice, suggesting the significance of the pain test, the strain, the route of the administration, or a combination of these. Therefore, our present study provides further support for potentiated antihyperalgesia during the continuous coadministration of two endogenous ligands acting at different receptors.
In summary, we have shown that adenosine and agmatine have low antinociceptive efficacy during continuous IT administration, but both of these ligands potentiate the effect of endomorphin-1 on nociception. We suggest that the physiological concentration of endomorphin-1 in the spinal cord may not be enough to produce a similar degree of enhancement to that seen after applying it in pharmacological doses. These results provide support for these endogenous ligands as important mediators of sensory information processing and suggest that these molecules represent novel targets for the therapeutic modulation of inflammatory pain; however, the systematic examination of side effects is essential.
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Acknowledgments
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Supported by Hungarian Scientific Grant (OTKA) T-34741 and Health Scientific Grant (ETT) 042/2001.
The authors thank Dr. Renate Schwarz from Pfizer Med-Inform for providing S(+)-ketamine for anesthesia. The authors are grateful to D. Durham for linguistic correction of the manuscript.
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Accepted for publication August 21, 2003.
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Abstract
Introduction
