title: Analgesia, enhancement of spinal morphine antinociception, and inhibition of tolerance by ultra-low dose of the α2A-adrenoceptor selective antagonist BRL44408.
abstract: Ultra-low doses of non-selective α2-adrenoceptor antagonists augment acute spinal morphine antinociception and block morphine tolerance; however, the receptor involved in mediating these effects is currently unknown. Here, we used tail flick and paw pressure tests on the rat to investigate the acute analgesic and tolerance-inducing effects of spinal morphine and norepinephrine alone or in combination with an ultra-low dose of the α2A-adrenoceptor antagonist, BRL44408. We also assessed the potential antinociceptive effects of BRL44408 alone following spinal administration. A spinal dose of BRL44408, over 1000-fold lower than that required to inhibit clonidine-induced antinociception (1.65ng/10µL), significantly prolonged morphine and norepinephrine action in both nociception tests. Following repeated morphine or norepinephrine injections, 1.65ng BRL44408 attenuated both the decline of antinociceptive effect and increase in morphine ED50 values, responses indicative of acute morphine tolerance. BRL44408 administered alone produced a delayed antinociceptive effect unrelated to repeated nociceptive testing. This response was partially reduced by the α2-adrenoceptor antagonist atipamezole (10µg). Ultra-low dose BRL44408 was able to inhibit the loss of morphine- and norepinephrine-induced antinociceptive response, and prevent the loss of drug potency due to repeated agonist exposure. This implicates the spinal α2A-adrenoceptor subtype in the action of ultra-low dose α2-adrenoceptor antagonists on morphine and norepinephrine tolerance. The BRL44408-induced analgesia is partially dependent on its interaction with the α2-adrenoceptors. Thus, this agent class may be useful in pain therapy.
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Queen׳s University, 76 Stuart Street, Kingston, Ontario, Canada, K7L 2V7. Electronic address: milneb@queensu.ca.
authors.forename: Brian
authors.initials: B
authors.lastname: Milne
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Queen׳s University, 76 Stuart Street, Kingston, Ontario, Canada, K7L 2V7; Department of Biomedical and Molecular Sciences, Queen׳s University, 18 Stuart Street, Kingston, Ontario, Canada.
authors.forename: Khem
authors.initials: K
authors.lastname: Jhamandas
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen׳s University, 18 Stuart Street, Kingston, Ontario, Canada.
authors.forename: Maaja
authors.initials: M
authors.lastname: Sutak
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen׳s University, 18 Stuart Street, Kingston, Ontario, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Grenier
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen׳s University, 18 Stuart Street, Kingston, Ontario, Canada; Department of Anesthesiology and Perioperative Care, University of California, 837 Health Sciences Road, Zot 4265, Irvine, CA, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000698:Analgesia / Q000379:methods; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004361:Drug Tolerance; D007093:Imidazoles / Q000494:pharmacology; D007278:Injections, Spinal / Q000379:methods; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D059408:Pain Management / Q000379:methods; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000700:Analgesics; D007093:Imidazoles; D011941:Receptors, Adrenergic; C050701:atipamezole; D009020:Morphine; D003000:Clonidine; D009638:Norepinephrine
keywords: Analgesia; Atipamezole (PubChem CID: 71310); BRL44408; BRL44408 (PubChem CID: 121850); Clonidine (PubChem CID: 2803); Morphine; Morphine (PubChem CID: 5288826); Norepinephrine; Norepinephrine (PubChem CID: 439260); α(2)-adrenoceptor antagonist; α(2A)-adrenoceptor