radolmidine and Pain

Fadolmidine (MPV-2426) is a novel alpha2 -adrenoceptor (alpha2) -AR) agonist developed for spinal analgesia. It is highly selective for alpha2 -ARs, but it lacks subtype selectivity. Due to its pharmacokinetic properties, it only poorly penetrates blood-brain barrier or spreads from the site of injection within the central nervous system. By intrathecal (i.t.) administration to laboratory animals, fadolmidine produces dose-dependent antinociception in healthy controls and in models of inflammatory, postoperative and neuropathic pain. Fadolmidine has been effective against various submodalities of pain such as heat pain, mechanical pain, and visceral pain. In general, the antinociceptive potency of fadolmidine, i.t., was equal to that of dexmedetomidine. At antinociceptive i.t. doses fadolmidine did not suppress motoneurons or responses to innocuous stimulation. It produced no hemodynamic depression and considerably less sedation than dexmedetomidine. By peripheral administration fadolmidine had no or only a weak antinociceptive action, except following nerve injury, particularly that of the postganglionic sympathetic nerve fibers. Together these experimental animal studies indicate that i.t. administration of fadolmidine provides a segmentally restricted treatment of somatic and visceral pain, with only minor cardiovascular and sedative side effects. Additionally, peripheral administration of fadolmidine might provide a selective treatment for some hypersensitivity states that involve dysfunction of the sympathetic nervous system.

Topics: Adrenergic Agonists; Adrenergic alpha-2 Receptor Agonists; Analgesics; Animals; Dose-Response Relationship, Drug; Humans; Hydrolyzable Tannins; Imidazoles; Indans; Injections, Spinal; Pain; Rats; Tannins

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.. 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.. 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.. 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.

Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Arthritis, Experimental; Dose-Response Relationship, Drug; Imidazoles; Indans; Injections, Intra-Articular; Male; Pain; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2

In the current study, the potency and spread of the antinociception induced by MPV-2426, a novel alpha2-adrenoceptor agonist, was characterized in neuropathic and non-neuropathic animals.. Neuropathy was induced by unilateral ligation of two spinal nerves in the rat. After lumbar intrathecal or systemic administration of MPV-2426, thermally and mechanically evoked responses of nociceptive neurons of the rostroventromedial medulla were recorded during pentobarbitone anesthesia. To obtain a behavioral correlate of neurophysiologic findings, nocifensor reflex responses evoked by thermal and mechanical stimuli were assessed in unanesthetized neuropathic and control animals.. After intrathecal administration, MPV-2426 and dexmedetomidine produced a dose-related antinociceptive effect, independent of the submodality of the noxious test stimulus or the pathophysiologic condition. This antinociceptive effect was spatially restricted to the inputs from the lower half of the body, and it was reversed by atipamezole, an alpha2-adrenoceptor antagonist. After systemic administration in non-neuropathic animals, MPV-2426 had no antinociceptive effect on responses to rostroventromedial medulla neurons, whereas systemically administered dexmedetomidine produced a dose-related suppression of nociceptive signals to the rostroventromedial medulla, independent of the site of test stimulation. In a behavioral study, intrathecal MPV-2426 produced a dose-dependent suppression of nocifensor responses evoked by noxious mechanical or heat stimuli, whereas systemic administration of MPV-2426 had no effects.. Intrathecal MPV-2426 has spatially limited antinociceptive properties in neuropathic and non-neuropathic conditions because of its action on spinal alpha2-adrenoceptors. These properties may be advantageous when designing therapy for spatially restricted pain problems.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Behavior, Animal; Dexmedetomidine; Electrophysiology; Hot Temperature; Imidazoles; Indans; Injections, Spinal; Male; Medulla Oblongata; Pain; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Rats, Wistar; Reaction Time; Signal Transduction

Intrathecally administered alpha2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Radolmidine is a novel alpha2-adrenoceptor agonist with a different pharmacokinetic profile compared with the well-researched dexmedetomidine. This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls.. Male Sprague-Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity-vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 microg, 2.5 microg, 5 microg, and 10 microg.. In the tail flick test, radolmidine showed a dose-dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 microg or 5 microg of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 microg dexmedetomidine-radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The two drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor acitivity-vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine.. Radolmidine and dexmedetomidine had equipotent antinociceptive effects in all tests studied. However, radolmidine caused significantly less sedation than dexmedetomidine, probably because of a different pharmacokinetic profile.

Topics: Adrenergic alpha-Agonists; Animals; Area Under Curve; Constriction; Dexmedetomidine; Imidazoles; Indans; Inflammation; Injections, Spinal; Male; Models, Biological; Motor Activity; Pain; Rats; Rats, Sprague-Dawley; Spinal Nerves; Structure-Activity Relationship