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CLONIDINE HAS ANESTHETIC-LIKE EFFECT ON PERIPHERAL NERVE NOT MEDIATED BY ALPHA2 ADRENOCEPTOR Jared T. Wilsey1 and David A. Provenzano2 1Medtronic Biologics, Memphis, TN and 2Pain Diagnostics Interventional Health Care, Sewickley, PA
RESULTS
BACKGROUND Clinical and non-clinical evidence demonstrates that clonidine has peripheral analgesic effects distinct from those that can be explained by systemic absorption and distribution to the CNS. These effects are presumably mediated by agonist activity at α2-adrenoceptors (α2ARs). Tissues relevant to inflammation and nociception have functional membrane α2ARs, including peripheral nerve endings, central synapses, and macrophages. However, a receptor-dependent mechanism precludes a direct effect on peripheral axons. While clonidine has been shown to have anti-nociceptive effects in neuropathic pain models, such models cannot differentiate direct effects on axons of the targeted nerve from receptor mediated effects on immunoinflammatory cells. Moreover, the possibility that diffusion of drug to peripheral nerve endings and/or the CNS contributes to effects in small animal models cannot be excluded.
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METHODS Peripheral nerve function was assessed by evoked action potentials (sciatic n.) as well as spinal somatosensory evoked potentials in male SD rats. The tibial nerve was stimulated with 10 mA constant current, delivered with GRASS™ platinum micro-electrodes placed just proximal to internal ankle. Recording electrodes were placed near the proximal sciatic nerve at the sciatic notch (ipsilateral and contralateral nerves) and over the L5 interlaminar space (spinal). Measurements were obtained with a Biopac MP36 amplifier and data acquisition unit (Biopac Systems, Goleta, CA). Following collection of baseline data, test solutions were administered directly into the subparaneural compartment of the right sciatic nerve, approximately 5 mm proximal to the tibial/fibular bifurcation, using a Hamilton HPLC injection syringe (20 µL injection volume). Saline served as the negative control and commercial 2% lidocaine served as the positive control. Clonidine was administered at escalating doses including 50, 100, 200, and 500 µg (minimum n=3 per dose).
A
FIGURE 2: Sciatic nerve block duration (as assessed by time until induced action potential amplitude exceeds 50% of baseline). Data were analyzed by ANOVA (F=15.4, p
RESULTS
BACKGROUND Clinical and non-clinical evidence demonstrates that clonidine has peripheral analgesic effects distinct from those that can be explained by systemic absorption and distribution to the CNS. These effects are presumably mediated by agonist activity at α2-adrenoceptors (α2ARs). Tissues relevant to inflammation and nociception have functional membrane α2ARs, including peripheral nerve endings, central synapses, and macrophages. However, a receptor-dependent mechanism precludes a direct effect on peripheral axons. While clonidine has been shown to have anti-nociceptive effects in neuropathic pain models, such models cannot differentiate direct effects on axons of the targeted nerve from receptor mediated effects on immunoinflammatory cells. Moreover, the possibility that diffusion of drug to peripheral nerve endings and/or the CNS contributes to effects in small animal models cannot be excluded.
b***, c***, d** b***, c**, d* a*, b* a** a***
METHODS Peripheral nerve function was assessed by evoked action potentials (sciatic n.) as well as spinal somatosensory evoked potentials in male SD rats. The tibial nerve was stimulated with 10 mA constant current, delivered with GRASS™ platinum micro-electrodes placed just proximal to internal ankle. Recording electrodes were placed near the proximal sciatic nerve at the sciatic notch (ipsilateral and contralateral nerves) and over the L5 interlaminar space (spinal). Measurements were obtained with a Biopac MP36 amplifier and data acquisition unit (Biopac Systems, Goleta, CA). Following collection of baseline data, test solutions were administered directly into the subparaneural compartment of the right sciatic nerve, approximately 5 mm proximal to the tibial/fibular bifurcation, using a Hamilton HPLC injection syringe (20 µL injection volume). Saline served as the negative control and commercial 2% lidocaine served as the positive control. Clonidine was administered at escalating doses including 50, 100, 200, and 500 µg (minimum n=3 per dose).
A
FIGURE 2: Sciatic nerve block duration (as assessed by time until induced action potential amplitude exceeds 50% of baseline). Data were analyzed by ANOVA (F=15.4, p
