BACKGROUND: Previous studies suggest that systemic administration of agmatine, endogenous ligand for imidazoline receptors has anti-hypernociceptive effects in experimental animal. However the peripheral effects of agmatine on inflammatory pain have not yet been elucidated. Here we examined the effects of intra-articular injection of agmatine in the induction and maintenance phase of arthritic pain. In addition, we sought to determine the potential contribution of imidazoline and alpha(2)-adrenergic receptors to the antinociceptive effects using clonidine which is mixed alpha(2)-adrenoceptor and imidazoline receptor agonist. METHODS: To induce arthritis in rats, 2% lambda-carrageenan (50microliter, in saline) was injected into the joint of the right hind limb under enflurane anesthesia. Either agmatine (10, 50, 100microgram/40microliter) or clonidine (10, 50, 100microgram/40microliter) was injected into the knee joint cavity immediately before or 4 hr after carrageenan injection. Weight load tests were performed to measure pain-related behavior in freely walking rats. RESULTS: The intraarticular injection of agmatine into the knee joint had no effects in the both phase of induction and maintenance of arthritic pain at any dose tested. However, injection of clonidine reversed arthritic pain, when injected 4 h after carrageenan injection. CONCLUSIONS: In rats, agmatine has no peripheral effect on inflammatory pain and imidazoline receptors in the periphery may not contribute to the anti-inflammatory pain.
Agmatine ; Anesthesia ; Animals ; Arthritis ; Carrageenan ; Clonidine ; Enflurane ; Extremities ; Imidazoline Receptors ; Inflammation ; Injections, Intra-Articular ; Joints ; Knee ; Knee Joint ; Rats ; Walking

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.
Adrenergic Agonists ; Animals ; Catheters ; Clonidine ; Hair ; Humans ; Hyperalgesia* ; Imidazoline Receptors* ; Ligation* ; Male ; Nervous System ; Rats* ; Rats, Sprague-Dawley ; Receptors, Adrenergic* ; Spinal Nerves ; Yohimbine ; Brimonidine Tartrate

BACKGROUND: The use of ketamine as the sole anesthetic induces marked central sympathetic stimulation, causing an increase of heart rate and blood pressure. alpha2-receptor agonist has been demonstrated to attenuate many of these undesirable effects when used as a premedicant. Brimonidine is a new and highly selective alpha2-receptor agonist, and rauwolscine is a selective alpha2-receptor antagonist with little affinity for imidazoline receptors. Using power spectral analysis of heart rate variability, this study examines the effect of brimonidine premedication during ketamine anesthesia on the changes in the autonomic nervous system. METHODS: From 57 Sprague-Dawley rats, 12 rats were anesthetized by urethane (U Group, 1.5 g/kg), 18 rats by ketamine (K Group, 100 mg/kg, 2 mg/kg/min continuous infusion) intraperitoneal injection after saline premedication. Brimonidine (BK Group, 30 microgram/kg, n=15), brimonidine with rauwolscine (BRK Group, 30 microgram/kg, 20 mg/kg, n=12) were adminstered as a premedicant before induction of ketamine anesthesia. ECG signals were recorded for 5 min after a period of 10 min of anesthetic stabilization. Power spectal analysis of the data was computed, using short-time Fourier transform. The spectral peaks within each measurement were calculated; a low frequency area (0.04~1.0 Hz), a high frequency area (1.0~5.0 Hz), and a total frequency area (0.04~5.0 Hz) were measured. RESULTS: The results documented that the K Group showed sympathetic activation as compared with the U Group (p<0.001). The BK Group showed sympathetic depression compared with the K and BRK Groups (p<0.001). There were no significant differences in sympatho-vagal balance between the K and BRK Groups. CONCLUSIONS: These results suggest that premedication with brimonidine is effective in attenuating the sympathetic stimulatory effect of ketamine.
Anesthesia* ; Animals ; Autonomic Nervous System ; Blood Pressure ; Depression ; Electrocardiography ; Fourier Analysis ; Heart Rate ; Imidazoline Receptors ; Injections, Intraperitoneal ; Ketamine* ; Premedication* ; Rats ; Rats, Sprague-Dawley ; Sympathetic Nervous System* ; Urethane ; Yohimbine ; Brimonidine Tartrate