Sherman, Stephen Edward (1994) Development and pharmacological characterization of an acute model of allodynia in the anesthetized rat. Doctoral (PhD) thesis, Memorial University of Newfoundland.
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The acute blockade of spinal glycinergic inhibition with intrathecal strychnine (i.t. STR; a glycine antagonist) in rats produces a change in somatosensory processing which resembles allodynia, a symptom of clinical neural injury pain. In the present study, the effects of i.t. STR were examined in urethane-anesthetized rats. Noxious paw pinch (PP) , or tail immersion (TI) in 55°C water, evoked a pronounced pressor response, tachycardia, a motor withdrawal reflex and de synchronization of the electroencephalogram (EEG) . Non-noxious, hair deflection (HD) , applied to the back, flanks, legs and tail of the rat, elicited only minor cardiovascular responses. Following i.t. STR (40 μg) , an identical HD stimulus evoked responses resembling those seen with noxious stimuli: an increase in mean arterial blood pressure (M.A.P) , tachycardia and a motor withdrawal reflex. All manifestations of this HD-evoked, STR-dependent allodynia were: 1) observed only with a light plane of anesthesia (as determined by EEG), 2) reversible with time (within 15-30 minutes) , 3) observed without convulsions, 4) evoked only when HD was applied to cutaneous dermatomes with innervation from spinal segments near the i.t. STR injection site (segmental), and 5) i.t STR dose-dependent (10-50 μg) . I.t. glycine produced dose-dependent inhibition of all indices of STR-dependent allodynia with ED₅₀ and 95% C.I. values of 609(429-865), 694(548-878) and 549 (458-658) μg for inhibition of heart rate (HR) increases, M.A.P. increases and motor withdrawal reflexes, respectively. I.t. betaine (a glycine derivative) also dose-dependently inhibited STR-dependent allodynia, possibly through metabolism to glycine. The ED₅₀ and 95% C.I. values were 981(509-1889), 1045(740-1476) and 1083(843-1391) μg for inhibition of HR, M.A.P. and motor withdrawal responses, respectively. EEG synchrony was unaffected by i.t. glycine or i.t. betaine. Neonatal capsaicin (25 mg/kg, s.c, post-natal day (PND) 1, and 50 mg/kg, s.c, PND 2, 3, 4, 11, 25, 55 and 85) significantly attenuated responses evoked by mechanical (PP), thermal (TI) or chemical (topical xylene) noxious stimuli, but did not affect STR-dependent allodynia. All indices of STR-dependent allodynia were also unaffected by i.t. morphine at a dose (50 μg, i.t.) which completely abolished responses evoked by noxious TI or PP. STR-dependent allodynia was dose-dependently suppressed by i.t. γ-D-glutamylglycine (DGG; nonselective excitatory amino acid [EAA] antagonist) and i.t. 2,3 -dihychroxy-6-nitro-7-sulf amoyl-benzo (f) quinoxaline (NBQX, AMPA receptor antagonist). The ED₅₀'s and 95% C.I. values for DGG against HD-evoked, STR-dependent HR, M.A.P. and motor responses were 15.6 (11.3-21.6), 16.9 (11.7-24.3) and 8.1 (5.2-12.5) μg, respectively. The corresponding values for NBQX were 12.2 (6.8-21.8), 14.4 (8.6-24.0) and 10.4 (5.5- 19.6) μg. EEG synchrony was unaffected by i.t. DGG or i.t. NBQX. The results of the present study indicate that glycine plays an important role in the spinal modulation of non-nociceptive input and supports the hypothesis that a loss of glycinergic modulation may underlie allodynia. The failure of i.t. morphine and neonatal capsaicin to prevent STR-dependent allodynia indicates that this phenomenon is initiated by primary afferent neurons not normally involved in nociception, presumably Αβ-fibers. The sensitivity of STR-dependent allodynia to both NMDA and non-NMDA receptor antagonists, and the failure of i.t. STR to produce hyperalgesia to mechanical, thermal or chemical noxious stimuli, confirm the independence of nociceptive pathways and STR-sensitive input in this model. The i.t. STR model allows the investigation of an important symptom of neural injury pain (opioid-resistant allodynia) in anesthetized animals, without having to inflict injury or to expose a conscious animal to aversive painful conditions, and might provide a useful alternative to chronic conscious animal models of allodynia.
|Item Type:||Thesis (Doctoral (PhD))|
|Additional Information:||Bibliography: leaves -162|
|Department(s):||Medicine, Faculty of|
|Library of Congress Subject Heading:||Allodynia; Excitatory amino acids; Glycine; Strychnine; Nervous system--Wounds and injuries; Pain|
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