The Antinociceptive and Antiallodynic Effects by Brimonidine, a Selective alpha2 Adrenergic Agonist / 대한마취과학회지

BACKGROUND: Clonidine, an alpha2 adrenoceptor agonist, has been known to have antinociceptive and antiallodynic effects. The antinociceptive and antiallodynic effects of brimonidine, a new selective alpha2 agonist, have not been evaluated yet in rats. Behavioral tests were performed to investigate the effects of systemically and spinally administered brimonidine on nociception and mechanical allodynia and the effect of spinal nerve ligation (SNL) on antinociception. METHODS: Rats were prepared with tight ligation of spinal nerves and/or a lumbar intrathecal catheter implantation. Using a hot plate (HP) test or von Frey hair (VFH) test, the effect of intraperitoneal (I.P.) and intrathecal (I.T.) brimonidine in normal and SNL rats were examined. I.P. brimonidine (100 - 1,000 microgram) and I.T. brimonidine (0.1 - 3.0 microgram) were given to examine the antinociceptive effect on an HP test. After a SNL, a HP test was conducted at the same doses of brimonidine to compare with the preoperative state. I.T. brimonidine (0.03 - 3.0 microgram) and saline (control) were administered to examine the antiallodynic effect in SNL rats. In addition, an antagonistic study with yohimbine 1.0 mg/kg I.P. was performed to investigate the reversal of the antiallodynic effect of brimonidine. Allodynic thresholds for lesioned hindpaw withdrawl to a VFH test were assessed and converted to %MPE. RESULTS: I.P. brimonidine produced an antinociceptive effect, and I.T. brimonidine also produced a significant antinociceptive effect (P < 0.05). After an SNL, I.T. brimonidine produced a dose-dependent antinocicpetive effect. In addition, I.T. brimonidine produced a dose-dependent antiallodynic effect which is antagonized by yohimbine (P < 0.05). CONCLUSIONS: The results suggest that brimonidine has a more potent antiallodynic effect when given intrathecally.

The Mechanism of Antiallodynic Effect of Intrathecal Morphine in Neuropathic Pain Induced by Spinal Nerve Ligation / 대한마취과학회지

BACKGROUND: Although the efficacy of morphine in a neuropathic pain state is somewhat controversial, intrathecally administered morphine reversed the mechanical allodynia in a previous animal study. Using a behavioral test, we investigated the mechanism of the antiallodynic action of intrathecal morphine by administering opioids, alpha2 adrenergic and cholinergic receptor antagonists in a rat model of neuropathic pain induced by a spinal nerve ligation injury. METHODS: Male Sprague Dawley rats were prepared with a tight ligation of the left lumbar 5th and 6th spinal nerves and insertion of a chronic lumbar intrathecal catheter. Morphine 1 microgram was administered intrathecally to attenuate the mechanical allodynia. Naloxone 10 microgram, yohimbine 30 microgram, prazosin 30 microgram, atropine 10 microgram, pirenzepine 10 microgram, and methoctramine 10 microgram was administered intrathecally before and after the injection of morphine in order to investigate the reversal of an increased allodynic threshold by morphine. The allodynic thresholds for the left hindpaw withdrawal to von Frey hairs were assessed and converted to %MPE. RESULTS: A reduction of mechanical allodynia by intrathecal morphine was produced. Naloxone pretreatment, but not posttreatment, reversed the antiallodynic effect of intrathecal morphine (P < 0.01). All alpha2 adrenergic and cholinergic receptor antagonists used here did not reverse it. CONCLUSIONS: The results suggest that the reversal mechanism of mechanical allodynia by intrathecal morphine appears to be mediated mostly by the opioid receptor system, but not the alpha2 adrenergic and cholinergic receptor systems, at the spinal level in a rat model of a spinal nerve ligation injury.

The Effect of alpha2 Adrenoceptors and Imidazoline Receptors on the Mechanical Allodynia in Rats with Nerve Ligation Injury / 대한마취과학회지

BACKGROUND: Clonidine, an alpha2 adrenoceptor agonist, has been known to have an antiallodynic effect in many animal and human studies. Clonidine, however, acts on imidazoline receptors as well as alpha2 adrenoceptors. Recently, the effect of clonidine on the symapthetic nervous system was reported to be mediated via the activation of the imidazoline receptor system but not the alpha2 adrenergic receptor system. Therefore, we conducted a behavioral test to investigate the effects of alpha2 adrenoceptors and imidazoline receptors on mechanical allodynia in rats with spinal nerve ligation (SNL) injury. METHODS: Male Sprague Dawley rats were prepared with tight ligation of the left lumbar 5th and 6th spinal nerves and chronic lumbar intrathecal catheter implantation for drug administration. Using a von Frey hair (VFH) test, we examined the effects of intrathecal (IT) brimonidine (0.03 - 3 microgram), clonidine (3 - 10 microgram), and rilmenidine (1 - 30 microgram) in SNL rats. Measurements of the baseline value VFH test was conducted at each dose to compare with the preoperative state. In addition, an antagonistic study with rauwolscine or yohimbine was performed to investigate the reversal of antiallodynic effects of each agonist. Allodynic thresholds for the withdrawal response of the left lesioned hindpaw to VFH stimuli were assessed and converted to %MPE. RESULTS: The antiallodynic effects of brimonidine, clonidine, and rilmenidine were produced in a dose dependent manner. The antiallodynic effects of IT brimonidine but not rilmenidine were significantly antagonized by alpha2 antgonists rauwolscine and yohimbine (P < 0.05). CONCLUSIONS: The results suggest that mechanical allodynia produced by a SNL injury is reduced by an imidazoline receptor agonist as well as alpha2 adrenergic receptor agonists and sympathetic activation is more likely mediated by spinal imidazoline receptors.

The Mechanism of Action of Intrathecal Morphine in Neuropathic Pain Induced by Nerve Ligation: The Effect of Naloxone / 대한마취과학회지

BACKGROUND: Although the efficacy of morphine in the neuropathic pain state is somewhat controversial, spinally administered morphine reversed the tactile allodynia in our previous animal study. Using a von Frey filament test, we examined the mechanism of action of intrathecal morphine by administration of the opioid receptor antagonist naloxone in a rat model of neuropathic pain induced by nerve ligation injury. METHODS: Male Sprague Dawley rats were prepared with tight ligation of the left lumbar 5th and 6th spinal nerves and a chronic lumbar intrathecal catheter. Intrathecal doses (0.3 and 1 microgram) of morphine were administered to attenuate the allodynic state. Naloxone was administered intrathecally (10 microgram) or intraperitoneally (30 and 150 microgram) in order to investigate the reversal of the antiallodynic effect of morphine. Allodynic thresholds for left hindpaw withdrawal to the von Frey hairs test were assessed and converted to %MPE. RESULTS: A reduced effect of tactile allodynia by intrathecal morphine was produced. Naloxone 10 microgram (IT) and 150 microgram (IP), but not naloxone 30 microgram (IP), reversed the antiallodynic effect of intrathecal morphine (P < 0.05). CONCLUSIONS: The results suggest that the mechanism of tactile antiallodynia induced by intrathecal morphine may include the opioid receptor system at the spinal and supraspinal level in a rat model of nerve ligation injury.

The Role of Spinal NO on the Mechanical Allodynia in the Inflammation Model by Freund's Complete Adjuvant / 대한마취과학회지

BACKGROUND: The effect of spinal nitric oxide (NO) on mechanical allodynia brought about by Freund's complete adjuvant (FCA)-induced inflammation is not known. From our previous experiment nitric oxide synthase (NOS) inhibitor nitroG-L-arginine methyl ester (L-NAME) given intraplantarly during the induction period decreased a mechanical hyperalgesia occurring because of FCA-induced inflammation. Therefore, we investigated the spinal effect of NO on mechanical allodynia after the development of allodynia produced by FCA-induced inflammation in rats. METHODS: Male Sprague Dawley rats were prepared with lumbar intrathecal catheter implantation. Inflammation was induced in the rats by injecting 0.1 ml of FCA under halothane anesthesia. Behavioral tests were done 1, 3, 6, 24, and 48 hours after injection of FCA. In the other group, intrathecal L-NAME (10 microgram) was given prior to FCA injection to examine the effect of pretreatment. On postinjection day 2, either L-NAME (10 microgram) or methylene blue (10 and 30 microgram) was administered intrathecally after the baseline measurement. The withdrawal response on mechanical allodynia was assessed by applying von Frey filaments to the right lesioned hindpaw and contralateral paw (as control) at 15, 30, 45, 60, 90, and 120 minutes. Sodium nitroprusside was administered intrathecally to determine the reversal effect of increased threshold in the L-NAME group. RESULTS: Injection of FCA produced a significant mechanical allodynia over time. Pretreatment with L-NAME did not prevent such a mechanical allodynia. Intrathecal L-NAME, but not methylene blue, reduced the mechanical allodynia, which was reversed by sodium nitroprusside. CONCLUSIONS: Spinal NO is likely invloved in the mechanism of the development and maintenance of mechanical allodynia in a state of FCA-induced inflammation.