title: Intrathecal oxymetazoline does not produce neurotoxicity in the spinal cord of the rat.
abstract: To determine if intrathecal (i.t.) oxymetazoline (OXY) induces histological evidence of spinal neurotoxicity, male, Sprague-Dawley rats (300-450 g; implanted with an i.t. catheter) were treated with i.t. saline or 100 nmol OXY twice daily for 3 days, or 200 or 300 nmol OXY once daily for 3 days. Spantide (D-Arg1, D-Try7,9, Leu11-substance P; 0.067 nmol = 0.1 microgram, 0.167 nmol = 0.25 microgram or 0.334 nmol = 0.5 microgram) or capsaicin (0.164 mumol = 50 micrograms), given as a single i.t. injection, were used as positive controls. Animals were killed 12 h after the last injection of saline or OXY, and 72 h after spantide or capsaicin. Spinal cord sections (L1 and adjacent segments) were examined by light microscopy for changes in gross morphology, substance P-like immunoreactivity (SP-IR) and calcitonin gene related peptide-like immunoreactivity (CGRP-IR). All doses of i.t. OXY produced antinociception (tail-flick ED50 = 53.7 nmol, paw pressure withdrawal ED50 = 93.3 nmol). Rectal temperature decreased by 1.5-2.4 degrees C up to 12 h after 100 nmol of i.t. OXY. There were no signs of inflammation or necrosis, and no detectable loss or damage to either spinal afferents or motor neurons as judged by SP-IR and CGRP-IR structures in spinal cords of OXY-treated animals (all doses) as compared to i.t. saline controls. Spantide (0.1 microgram) had no antinociceptive or neurotoxic effect; 0.25 microgram induced irreversible loss of the TF reflex and transient hind limb paralysis; 0.5 microgram induced irreversible loss of TF and PP responses, permanent hind limb paralysis, bladder and bowel dysfunction. The spinal cords from these animals showed signs of extensive necrosis, cavitation, and haemorrhage in the ventral horn accompanied by a loss of CGRP-IR motor neurons. Capsaicin-treated rats exhibited a permanent loss of the TF but not the PP response and a marked reduction of SP-IR spinal afferents in the dorsal horn. It is concluded that i.t. OXY produces antinociception in the rat with no detectable spinal neurotoxicity as assessed by parameters which are sensitive to the neurotoxins, spantide and capsaicin.
authors.affiliation: School of Pharmacy, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Canada.
authors.forename: C W
authors.initials: CW
authors.lastname: Loomis
authors.forename: D
authors.initials: D
authors.lastname: Vyas
authors.forename: S E
authors.initials: SE
authors.lastname: Sherman
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005684:Gait; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D010109:Oxymetazoline / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology*; D011187:Posture; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000700:Analgesics; D009498:Neurotoxins; D013373:Substance P; D010109:Oxymetazoline; C042867:spantide; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin