Development and pharmacological characterization of an acute model of allodynia in the anesthetized rat

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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Abstract

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.

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