An isobolographic analysis of drug interaction between intrathecal clonidine and baclofen in the formalin test in rats
Introduction
Neuropathic pain syndromes are characteristically resistant to standard therapy with opioids (Arner and Meyerson, 1988), but sensitive to drugs which are considered to be weak analgesics in acute pain, e.g. α2-adrenoceptor or GABAB receptor agonists and N-methyl-d-aspartate (NMDA) receptor antagonists (Fromm et al., 1984, Tamsen and Gordh, 1984, Kristensen et al., 1992). The main characteristics of neuropathic pain syndromes are pain, dysesthesias and hyperalgesia. It is postulated that the central sensitisation or the wind-up phenomenon plays an important role in neuropathic pain syndromes (Yamamoto and Yaksh, 1992b).
An experimental model of injury-induced central sensitization is the formalin test; a biphasic nociceptive response, following subcutaneous injection of dilute formalin into the rat hind-paw, where phase 1 reflects an acute pain response, and phase 2 reflects the injury-induced spinal sensitisation and hyperalgesia (Coderre et al., 1990). Chaplan et al. (1997)demonstrated that the spinal sensitization observed in the formalin test has a similar mechanism to that of tactile hyperesthesia observed in the peripheral neuropathic pain model in rats. The nerve injury-induced tactile allodynia displayed a similar structure activity relationship to the formalin test with regard to blockade of the NMDA receptor by different NMDA antagonists. Although NMDA antagonists are known to produce motor dysfunction at antinociceptive doses, the powerful synergy observed between spinal MK-801, an NMDA antagonist, and clonidine in the peripheral neuropathic pain rat model may possess some clinical significance (Lee and Yaksh, 1995). Recently, the spinal γ-aminobutyric acid (GABA) system has been implicated in antinociceptive mechanisms of neuropathic pain (Smith et al., 1994).
It has been shown that another α2-adrenoceptor agonist, 2-(2,6-diethyl-phenylamino)-2-imidazoline (ST-91) and the GABAB receptor agonist baclofen, administered intrathecally (IT), produced a dose-dependent inhibition of both phases of the formalin response at doses not affecting motor function (Malmberg and Yaksh, 1993a, Dirig and Yaksh, 1995). Clonidine and baclofen are clinically used by IT route (Tamsen and Gordh, 1984Pen 1992). However, these drugs have not been studied together. Therefore, we decided to study the antinociceptive effect of clonidine and baclofen in the formalin test.
Section snippets
Animals
Male Wistar rats (260–350 g), purchased from a licensed dealer (T. Górzkowska, Warsaw, Poland), were used. The rats were housed in groups of eight per cage on a natural light/dark cycle, with free access to water and food. All testing was performed between 10:00 and 15:00 h.
Drugs and treatment
The following drugs were used in this study: clonidine (clonidine HCl; MW: 266.6; Sigma, St Louis, MO), baclofen ((±)-baclofen; MW: 213.7; RBI, Natick, MA) and atipamezole (MW: 348.5; Orion Farmos, Turku, Finland). Drugs
The effects on the formalin test
The magnitude of the behavioral response in both phases of the formalin test did not differ in the control groups (IT solvent) over the time of the study (one-way ANOVA, P>0.05). Therefore, the control experiments were pooled and employed as a common control group.
The IT clonidine and baclofen resulted in a dose-dependent inhibition of the formalin response (Fig. 1Fig. 2). A typical time course of this effect, with different doses of clonidine and baclofen, given 15 min before the injection of
Discussion
The results of the present study demonstrate that: (1) IT administration of clonidine or baclofen, at doses that do not affect motor performance, produces a significant, dose-dependent, suppression of the formalin-induced response in rats, and (2) clonidine and baclofen, co-administered IT, produce greater antinociception than predicted by a simple addition of their effects (synergy) in phase 2 of the formalin test in rats.
Injection of formlin into the paw of an animal produces a biphasic
Acknowledgements
This study was supported by a grant from the Medical University School in Lublin No. 90/96. The study design was approved by the ethical committee for animal research at the Medical University School in Lublin.
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