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Anesth Analg 2007;105:245-250
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000265850.08385.a6

ANALGESIA

Section Editor:
Tony L. Yaksh

Peripheral Suppression of Arthritic Pain by Intraarticular Fadolmidine, an {alpha}2-Adrenoceptor Agonist, in the Rat

Osei B. Ansah, DVM, PhD, and Antti Pertovaara, MD, PhD

From the Biomedicum Helsinki, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland.

Address correspondence and reprint requests to A. Pertovaara, MD, PhD, Biomedicum Helsinki, Institute of Biomedicine/Physiology, POB 63, University of Helsinki, FIN-00014 Helsinki, Finland. Address e-mail to antti.pertovaara{at}helsinki.fi.

Abstract

BACKGROUND: Earlier results suggest that peripheral {alpha}2-adrenoceptors and opioid receptors may reduce arthritic pain. Fadolmidine is a highly selective {alpha}2-adrenoceptor agonist that has only limited central access after peripheral administration. We assessed the peripheral antinociceptive properties of fadolmidine and the potential contribution of peripheral opioid receptors to its antinociceptive effect in experimental monoarthritis.

METHODS: After induction of monoarthritis in the knee joints of rats, we determined the frequency of vocalization induced by repetitive movement of the knee joint. Fadolmidine and clonidine were administered intraarticularly ipsi- or contralateral to the inflamed joint. Reversal of the fadolmidine-induced effect was attempted with subcutaneous (s.c.) administration of atipamezole, an {alpha}2-adrenoceptor antagonist, and intraarticular administration of naloxone methiodide, an opioid receptor antagonist that does not penetrate the blood–brain barrier.

RESULTS: Fadolmidine produced a dose-dependent attenuation of the vocalization response to movement of the inflamed knee joint, and this effect was significantly stronger after ipsi- than contralateral drug administration. Clonidine also produced a dose-dependent attenuation of the vocalization response, but this effect was not significantly different after ipsi- versus contralateral drug administration. Fadolmidine-induced antinociception was reversed by s.c. administration of atipamezole. Furthermore, intraarticular administration of naloxone methiodide into the inflamed, but not the contralateral, joint reversed the antinociceptive effect of fadolmidine independent of whether fadolmidine was administered into the inflamed or contralateral joint.

CONCLUSIONS: In rats, intraarticular administration of fadolmidine provides a marked suppression of pain-related behavior in arthritis, due to a selective action on peripheral {alpha}2-adrenoceptors and opioid receptors.

Earlier studies indicate that intraarticular administration of clonidine, a prototype {alpha}2-adrenoceptor agonist, attenuates arthroscopy-induced pain in humans (1–6) and arthritic pain-related behavior in experimental animals (7). Although clonidine rapidly spreads to the central nervous system (CNS) after peripheral administration (8), peripheral mechanisms might contribute to its pain-alleviating effect. This is suggested by the finding that intraarticular administration of apraclonidine, a clonidine derivative that has limited access to the CNS, proved equally effective in reducing arthroscopy-induced pain as did clonidine (9).

Fadolmidine (or MPV-2426) is a highly selective and potent {alpha}2-adrenoceptor agonist that spreads poorly through the blood–brain barrier (10). Intraarticular administration of fadolmidine provides a possibility for selective activation of peripheral {alpha}2-adrenoceptors with little, if any, activation of central {alpha}2-adrenoceptors. Thus, intraarticular treatment of arthritic pain with fadolmidine, if effective, might provide selective analgesia without centrally mediated side effects such as hypotension and sedation. In the present study, we characterized the antinociceptive effect induced by intraarticular administration of fadolmidine in experimental monoarthritis in the rat. Furthermore, since intraarticular administration of morphine may also suppress pain induced by arthroscopy (11,12) or arthritis (13,14), we determined the possible contribution of peripheral opioid receptors to the antinociceptive effect induced by peripherally administered fadolmidine in experimental monoarthritis.

METHODS

This study was approved by the Institutional Ethics Committee of the University of Helsinki and Regional Government of Southern Finland. The experiments were performed according to the guidelines of the European Communities Council Directive of November 24, 1986 (86/609/EEC). Male Hannover–Wistar rats (Harlan, Horst, Netherlands) weighing 200–300 g were used in this study. The rats were kept in a room with a 12-h alternating light/dark cycle and had access to food and water ad libitum. They were allowed some time (4–7 days) to acclimate to their new environment in the laboratory before the start of experiments. During this habituation period, the animals were exposed daily to identical handling as during the actual experiments. After habituation, the animals did not vocalize in response to handling, restraint, or movement of a healthy joint. The {alpha}2-adrenergic test drugs were fadolmidine (MPV-2426, an {alpha}2-adrenoceptor agonist that spreads poorly to the CNS after peripheral administration; Orion Pharma, Inc., Espoo, Finland) (10), atipamezole (an {alpha}2-adrenoceptor antagonist that rapidly spreads through the blood–brain barrier; OrionPharma) (15), and clonidine (the prototype {alpha}2-adrenoceptor agonist that rapidly spreads to the CNS after peripheral administration (8); Sigma Chemical Co., St. Louis, MO). These {alpha}2-adrenergic compounds are not selective for the subtypes of the {alpha}2-adrenoceptor. Furthermore, test drugs included naloxone methiodide (an opioid receptor antagonist that spreads poorly to the CNS after peripheral administration; Sigma) and physiological saline. Before inducing arthritis, the rats were anesthetized with pentobarbital sodium (OrionPharma) administered intraperitoneally (i.p.) at 60 mg/kg. For the induction of arthritis, 0.1 mL of a mixture of 3% kaolin (Sigma) and 3% carrageenan (Sigma) was injected into the synovial cavity of the left knee joint. This joint was subsequently manipulated by flexion and extension for about 1 min. Circumference of the knee joint was measured with a string before and 1 day after the induction of arthritis in 12 rats.

The rats were divided into 19 treatment groups (Table 1) with each rat assigned to only one group. Fadolmidine, clonidine, naloxone methiodide, and saline were injected intraarticularly either into the inflamed or contralateral joint, whereas atipamezole was injected subcutaneously (s.c.). Intraarticular injections of test drugs were performed without anesthesia using a fine 27-G hypodermic needle. The number of times that the rat vocalized after five flexion-extension movements of the knee joint ipsi- and contralateral to the inflammation was recorded and termed vocalization score. If the rat vocalized to each of the five consecutive limb movements, it got the maximum vocalization score of 100% representing the maximum amount of arthritic pain.


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  		Table 1. Experimental Groups

 

In actual testing sessions, the vocalization score was determined before inducing arthritis and 1 day after the induction of arthritis (further on referred to as day 2). On day 2, baseline values for these variables were recorded immediately before administering any test drug and additionally, at 30, 60, and 120 min after administering fadolmidine (10, 30, or 100 µg), clonidine (30 or 100 µg), or saline. When attempting reversal of fadolmidine-induced effects, rats received 1 mg/kg of atipamezole s.c., or naloxone methiodide at the dose of 10 or 20 µg intraarticularly 15 min before intraarticular administration of fadolmidine. The choice of drug doses was based on previous literature. Fadolmidine and clonidine are equipotent in some, but not all, assays (10). Since atipamezole spreads very effectively to the CNS after its peripheral administration (15), it was given only systemically and not intraarticularly. After completion of testing, the animals were killed by administering a lethal dose of pentobarbitone.

One-way or two-way analysis of variance (ANOVA) followed by Tukey test, or t-test (comparisons between two groups) were used to determine if there were significant differences between experimental conditions. For comparisons between doses, the value measured 30 min after administration of fadolmidine or clonidine was chosen. Results have been presented as mean ± sem. P < 0.05 was considered to represent a significant difference.

RESULTS

The kaolin-carrageenan mixture induced obvious acute inflammatory changes in the ipsilateral knee joint. One day after its injection, the ipsilateral knee joint swelled (circumference of the joint increased from 5.90 ± 0.19 cm before induction to 7.10 ± 0.35 cm; P = 0.008), became tender and warm. The rat readily vocalized upon slight manipulations of the arthritic limb and avoided placing much weight on this injured limb during spontaneous locomotion (gait). Extension of the knee joint produced no vocalization responses before inflammation or when the joint contralateral to the inflamed joint was extended.

Attenuation of Arthritic Pain by Intraarticular Fadolmidine
Intraarticular administration of fadolmidine into the inflamed joint produced a dose-related antinociceptive effect as indicated by a decrease in vocalization response to repeated extension and flexion of the arthritic limb (F2,88 = 48.18, P < 0.0001; Fig. 1A). The maximum antinociception was obtained within 30 min after intraarticular injection of fadolmidine and the duration of antinociception varied from 1 to at least 2 h, depending on the dose (Fig. 1A). Intraarticular fadolmidine produced a significantly stronger antinociception after administration into the arthritic than the contralateral joint (F1,30 = 30.29, P < 0.0001; Fig. 1B), independent of the dose (30 or 100 µg; F1,30 = 0.45). Systemic administration of atipamezole, an {alpha}2-adrenoceptor antagonist, at the dose of 1 mg/kg completely reversed antinociception induced by 100 µg of fadolmidine in the inflamed joint (Fig. 1B). Systemic administration of atipamezole (1 mg/kg) or intraarticular administration of saline alone had no effect on vocalization scores (Figs. 1A and B).


Figure 142
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  		Figure 1. Time course (A) and dose-dependence (B) of the antinociceptive effect induced by intraarticular administration of fadolmidine in the monoarthritic rat. Vocalization score indicates the mean vocalization response to repetitive movements of the inflamed knee joint by the experimenter (0% = no response, 100% = the maximum response; i.e., the rat gives a vocalization response every time the joint is moved). In A, Sal = saline control, Fad-30 and Fad-100 = fadolmidine administered at the dose of 30 or 100 µg. Time point 0 min represents the score immediately prior to drug administrations. In B, Ipsi = fadolmidine was administered into the inflamed joint, Contra = fadolmidine was administered into the joint contralateral to the inflamed one. The dose of 0 µg represents administration of saline control. +A = atipamezole administered subcutaneously at the dose of 1 mg/kg 15 min prior to intraarticular administration of fadolmidine at the dose of 100 µg into the inflamed joint. A = atipamezole administered subcutaneously alone at the dose of 1 mg/kg. **P < 0.01, ***P < 0.005 (Tukey test; reference: the corresponding predrug or 0 condition in A, and the saline or 0 group in B). +P < 0.05, ++P < 0.01 (difference between the ipsi- and contralateral treatment groups in B). The error bars represent sem (n = 4–18).

 

Attenuation of Arthritic Pain by Intraarticular Clonidine
Intraarticular administration of clonidine produced dose-related antinociception as indicated by a decrease in the vocalization response to repetitive extension and flexion of the arthritic limb (F2,21 = 24.58, P < 0.0001; Fig. 2A). The antinociceptive effect of clonidine was not significantly different after administration into the inflamed versus the contralateral knee joint (F1,21 = 0.30). When administered into the inflamed joint, clonidine and fadolmidine produced an equal antinociceptive effect (F1,35 = 0.52; Fig. 2B). However, when administered into the contralateral knee joint, clonidine produced a significantly stronger suppression of the vocalization response to repetitive movement of the inflamed joint than fadolmidine (F1,21 = 5.84, P < 0.03; Fig. 2C), independent of the drug dose (30 or 100 µg; F2,21 = 1.46).


Figure 242
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  		Figure 2. Attenuation of pain-related behavior in the monoarthritic rat by intraarticular administration of clonidine versus fadolmidine. (A) Clonidine was administered into the inflamed joint (Ipsi) or to the contralateral joint (Contra). (B) Clonidine (Clon) or fadolmidine (Fad) was administered into the inflamed joint. (C) Clonidine or fadolmidine was administered into the knee joint contralateral to the inflamed joint. In each graph, the vocalization response was assessed by repetitive movement of the inflamed joint. (0% = no response, 100% = the maximum response). Drug dose 0 µg represents intraarticular administration of saline. **P < 0.01, ***P < 0.005 (Tukey test; reference: the corresponding saline control group). +P < 0.05 (t-test; difference in the effect between corresponding doses of clonidine versus fadolmidine). The error bars represent sem (n = 4–18).

 

Contribution of Peripheral Opioid Receptors to Fadolmidine-Induced Antinociception
To study the contribution of peripheral opioid receptors to the {alpha}2-adrenergic attenuation of arthritic pain, naloxone methiodide, an opioid receptor antagonist that does not cross the blood–brain barrier, was administered intraarticularly 15 min before administration of fadolmidine. When administered into the inflamed joint, naloxone methiodide at the dose of 10 µg produced a significant attenuation of antinociception induced by 30 or 100 µg of fadolmidine in the inflamed joint (F1,49 = 43.39, P < 0.0001; Fig. 3A). The attenuation of antinociception induced by 100 µg of fadolmidine in the inflamed joint was not significantly different if the dose of naloxone methiodide in the inflamed joint was increased from 10 µg (n = 5) to 20 µg (n = 3), as indicated by vocalization scores to movement of arthritic limb after these doses (46 ± 8% vs 66 ± 10%, respectively; not shown).


Figure 342
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  		Figure 3. Reversal of fadolmidine-induced antinociception in the monoarthritic rat by naloxone methiodide, an opioid receptor antagonist that does not cross the blood–brain barrier. (A) Attempt to attenuate the antinociceptive effect of fadolmidine alone (Sal + Fad: Fadolmidine at the dose of 0, 30, or 100 µg) in the inflamed joint by administration of naloxone methiodide (10 µg) into the inflamed joint (Nal-10 + Fad). (B) Attempt to attenuate the antinociceptive effect of 100 µg of fadolmidine injected to the contralateral joint (Fad-100-Contra) by naloxone methiodide injected to the contralateral (Nal-10-contra + Fad) or inflamed (Nal-10-ipsi + Fad) joint. Vocalization score 100% represents the maximum response to repetitive movement of the inflamed knee joint and 0% no response. In reversal attempts, intraarticular administration of naloxone methiodide was performed at the dose of 10 µg 15 min before intraarticular administration of fadolmidine. In A, drug dose 0 µg represents intraarticular administration of saline in the Fad-alone group and intraarticular administration of 10 µg of naloxone methiodide alone in the Nal-10 + Fad group. **P < 0.01, ***P < 0.005 (Tukey test; reference: the corresponding saline control group in A and the Fad-100-contra group in B). +++P < 0.005 (t-test; comparison between Fad-alone and Nal-10 + Fad groups). The error bars represent sem (n = 4–18).

 

Contralateral administration of fadolmidine at the dose of 100 µg induced a significant attenuation of the vocalization response to movement of the arthritic limb (Fig. 1B). This antinociceptive effect induced by contralateral administration of fadolmidine was not attenuated by 10 µg of naloxone methiodide in the contralateral knee joint (Fig. 3B). However, 10 µg of naloxone methiodide in the inflamed knee joint significantly attenuated antinociception induced by contralateral administration of fadolmidine (Fig. 3B).

DISCUSSION

The results indicate that intraarticular administration of fadolmidine produces a dose-dependent suppression of arthritic pain-associated vocalization. This is in line with earlier findings reporting that intraarticular administration of clonidine or apraclonidine attenuates arthroscopy-induced pain in humans (1–6) and pain-related behavior in arthritic animals (7). Fadolmidine-induced attenuation of pain-related vocalizations in arthritic animals was obtained at intraarticularly administered doses (30–100 µg/animal) that are subantinociceptive in healthy animals and that produce few, if any central effects after peripheral administration (10). The finding that the antinociceptive effect of fadolmidine was significantly stronger after administration into the inflamed joint than to the contralateral joint supports the hypothesis that peripheral mechanisms had an important role in the antinociceptive action of fadolmidine in the monoarthritic rat. Moreover, reversal of fadolmidine-induced antinociception by intraarticular administration of naloxone methiodide, an opioid receptor antagonist that does not cross the blood–brain barrier, suggests that peripheral mechanisms played a major role in suppression of pain-related behavior by intraarticular fadolmidine in arthritic animals. The latter finding also indicates that peripheral opioid receptors contributed to fadolmidine-induced antinociception.

The suppression of a pain-related response to movement of the arthritic joint in this study, or suppression of secondary mechanical hyperalgesia in the arthritic limb in an earlier study (7), were identical after intraarticular administration of clonidine into the inflamed versus contralateral joint, whereas fadolmidine- induced antinociception was significantly stronger after ipsi- than contralateral administration. These findings indicate that the antinociceptive effect of fadolmidine is more restricted to the treated side than that of clonidine, which is in line with previously described pharmacokinetic differences between these two compounds (10). It is noteworthy that the antinociceptive effect induced by contralateral administration of fadolmidine was reversed by administration of naloxone methiodide in the inflamed, but not the contralateral, joint. This finding indicates that the attenuation of arthritic pain by contralateral as well as ipsilateral administration of fadolmidine can be explained by action on peripheral opioid receptors in the inflamed joint.

Peripheral administration of noradrenergic compounds may produce pain aggravation or attenuation, depending on the pathophysiological condition. There are several peripheral mechanisms through which an {alpha}2-adrenoceptor agonist might facilitate pain (16). However, there are also mechanisms through which an {alpha}2-adrenoceptor agonist may produce peripheral antinociception, which may explain the present findings. First, perineural application of an {alpha}2-adrenoceptor agonist has produced a local anesthetic effect under in vitro conditions (17,18). It has been shown, by whole cell patch clamp recordings in dorsal root ganglion neurons, that an {alpha}2-adrenoceptor agonist inhibits a hyperpolarization-activated inward (excitatory) current (Ih) (19). Since the hyperpolarization-induced inward current presumably facilitates the neuronal firing discharge, it has been proposed that the inhibition of a hyperpolarization-induced inward current (Ih) might contribute to the local anesthetic effect of {alpha}2-adrenoceptor agonists and explain peripheral {alpha}2-adrenergic antinociception (20). In the present study, reversal of fadolmidine-induced antinociception by intraarticular administration of naloxone methiodide, however, does not support the hypothesis that a direct action of fadolmidine on neuronal membrane, or its ionic channels explains peripheral antinociception in the inflamed knee joint. Second, an {alpha}2-adrenoceptor agonist might produce peripheral antinociception via action on the immune system. Previous studies indicate that an {alpha}2-adrenoceptor agonist may induce peripheral antinociception by altering the balance of pro- and antiinflammatory cytokines (21,22) and by inducing a release of endogenous opioids from immune cells (23). The latter finding is in agreement with the present and earlier observations (24,25) that a peripheral administration of an opioid receptor antagonist reverses the {alpha}2-adrenergic antihyperalgesic effect in inflamed tissues. In line with this, earlier studies indicate that peripheral opioid receptors may, indeed, reduce pain induced by arthroscopy (11,12) or arthritis (13,14). A serial activation of {alpha}2-adrenoceptors and opioid receptors may explain the lack of stronger analgesia by a combination of intraarticular morphine and clonidine than either drug alone in some (26), but not all (3) studies.

Inflammation-induced swelling potentially contributes to arthritic pain. {alpha}2-Adrenoceptors are present within articular blood vessels and their activation produces a modest vasoconstriction (27) that might reduce swelling and arthritic pain. Previous results indicate that intraarticular administration of an {alpha}2-adrenoceptor agonist, however, does not produce acute reduction in swelling of the inflamed joint (7). This finding suggests that antiinflammatory action is not likely to explain the acute antinociceptive effect of fadolmidine or clonidine in arthritic animals. It should be noted that there may be some differences in peripheral effects induced by prolonged and single administrations of an {alpha}2-adrenoceptor agonist in inflamed animals. This is indicated by the finding that repeated local administration of clonidine produced long-term attenuation of nerve injury-induced hypersensitivity, probably due to action on cytokines (21). Moreover, prolonged systemic administration of epinephrine reduced radiographically assessed joint injury in arthritic animals (28). In the present study, the duration of antinociception induced by a single intraarticular injection of fadolmidine could be explained by the pharmacokinetic properties of the drug.

Footnotes

Accepted for publication March 21, 2007.

Supported by grants from the Academy of Finland, Helsinki, and the Sigrid Jusélius Foundation, Helsinki, Finland.

Dr. A. Pertovaara has actively consulted with and performed experiments for OrionPharma, Inc.

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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 2007 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press