A study of the antinociceptive and toxicological effects of intrathecal dexmedetomidine and methoxamine in the rat

Maher, Sue Ellen (1998) A study of the antinociceptive and toxicological effects of intrathecal dexmedetomidine and methoxamine in the rat. Masters thesis, Memorial University of Newfoundland.

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    Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
    (Original Version)

Abstract

Alpha (α)-adrenergic agonists represent a novel drug class of spinal analgesics and are most commonly used in combination with local anesthetics and opioids. Spinal noradrenergic antinociception is mediated primarily by α₂- adrenoceptors, although α₁-adrenoceptor-mediated antinociception has never been disproven. As demonstrated vasoconstrictors, however, there are concerns regarding the safety of the spinal administration of α₁- and α₂- agonists, alone and in combination. -- The purpose of this study was to determine if intrathecal (i.t.) methoxamine (MX) (α₁-agonist) potentiates i.t. dexmedetomidine (DX) (α₂- agonist)-induced antinociception, if i.t. DX, alone and in combination with MX, injected twice daily for four days, causes spinal neurotoxicity, and the effect of a sub-toxic combination of i.t. DX and MX on i.t. dynorphin-induced neurotoxicity. Male, Sprague-Dawley rats (300-400g) implanted with i.t. catheters (L1 termination) were used throughout. The i.t injection of dexmedetomidine (0.01-µg) produced dose-dependent antinociception in the tail flick (TF) and paw pressure (PP) tests (ED₅₀ = 45 and 252 ng, respectively). The addition of a fixed dose of MX (10 µg i.t.), which produced <5% maximum percent effect (MPE) in the TF test and was inactive in the PP test, significantly shifted the DX dose response curve to the left (ED₅₀= 8.1 ng; TF test and 10 ng; PP test) but did not prolong DX's duration of action. A fixed dose combination of DX (0.025 µg) + MX (10 µg) producing near maximal antinociception in the TF test and intermediate activity in the PP test, was near completely blocked by prazosin (10 µg i.t.) or Wyeth 27127 (0.5 µg i.t.). -- Repeated i.t. injections of high dose DX (10 µg) and DX+MX (10 µg each) produced sedation but no motor dysfunction, no inflammation, haemorrhage or necrosis of the spinal cord. Immunohistochemical studies revealed no damage to or loss of calcitonin-gene-related peptide immunoreactivity(CGRP-IR) in either the dorsal or ventral horns or substance P immunoreactivity (SP-IR) in the ventral horn as compared to vehicle-treated rats. In contrast, dynorphin A₁₋₁₃ (192 µg;120 nmol) produced: 1) immediate and irreversible hindlimb paralysis; 2) loss of the stepping and tail flick reflexes; and 3) delayed bladder and bowel dysfunction. Forty-eight hours after dynorphin, immunohistochemical examination revealed a marked depletion of CGRP-IR motor neurons in the lumbar ventral horn. CGRP-or SP-IR was unchanged in the dorsal horn. -- To assess the effect of i.t. DX and MX, alone and in combination, on dynorphin neurotoxicity, rats were pretreated with i.t. DX, MX, a combination of DX+MX (10 µg each) or saline 15 min before i.t. dynorphin A₁₋₁₃(192 µg;120 nmol). In saline pretreated rats, dynorphin produced the same effects as described above. Pretreatment with i.t. DX, MX or DX+MX attenuated the hindlimb paralytic effect of dynorphin. Twenty-four hours after injection, motor reflexes were preserved and accelerating rotarod (RR) scores were similar to controls (no dynorphin) in 4 out of 5 DX-, 3 out of 5 MX- pretreated and 4 out of 4 DX+MX-pretreated rats. Histological evaluation of the spinal cords obtained from these rats were consistent with these functional results, indicative of a neuroprotective effect. For DX and DX+MX pretreated rats, there was a corresponding decrease in rectal temperature (up to 3.4°C for DX alone). MX did not alter rectal temperature. These results of this study indicate that 1) a threshold dose of i.t. MX potentiates α₂-mediated antinociception in the rat; 2) repeated spinal administration of this drug combination has no detectable neurotoxic effect and 3) pretreatment with these drugs effects neuroprotection against i.t. dynorphin in the rat.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/1403
Item ID: 1403
Additional Information: Bibliography: leaves 106-130
Department(s): Pharmacy, School of
Date: 1998
Date Type: Submission
Library of Congress Subject Heading: Agonists, Chemical; Alpha adrenoreceptors; Analgesia
Medical Subject Heading: Adrenergic alpha--Agonists; Analgesics; Injections, Spinal; Dexmedetomidine; Methoxamine; Rats

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