I Nakamura1, Y Ohta, O Kemmotsu. 1. Department of Anesthesiology and Intensive Care, Hokkaido University School of Medicine, Sapporo, Japan.
Abstract
BACKGROUND: Adenosine analogs have been shown to produce antinociception after intrathecal administration. To determine the adenosine receptor subtype involved in spinal antinociception, the effects of selective agonists and an antagonist on the evoked potentials recorded from a neonatal rat spinal cord were studied. The measured potentials are a slow ventral root potential (slow VRP), which is the C-fiber-evoked excitatory response associated with nociceptive information; a monosynaptic reflex (MSR), which reflects a non-nociceptive transmission related to motor function; and a dorsal root potential (DRP), which reflects a gamma-aminobutyric acidA (GABA(A)) receptor-mediated presynaptic inhibition associated with analgesia. METHODS: The evoked potentials were recorded in response to electric stimulation of a lumbar dorsal root. Dose-response curves of agonists for these responses were obtained to determine their relative potency order. The antagonist dissociation constants (K(D) values) were estimated by Schild analysis. RESULTS: Adenosine agonists dose dependently inhibited the slow VRP and the MSR. However, the slow VRP was five to eight times more sensitive to them than was the MSR. The rank order of agonist potency was N6-cyclohexyladenosine (CHA) = N6-(R)-phenylisopropyladenosine (R-PIA) > 5'-N-ethylcarboxamidoadenosine (NECA) >> CGS 21680 in both responses. 8-Cyclopentyltheophylline produced dose-dependent parallel shifts to the right of NECA dose-response curves for these responses. Schild analysis gave linear plots with slopes near unity. The K(D) values of CPT for the MSR and the slow VRP were estimated to be 5.5 nM and 4.3 nM, respectively. The DRP was also depressed by adenosine agonists with potency order of CHA > NECA >> CGS 21680. 8-Cyclopentyltheophylline antagonized the inhibitory effects of CHA on the DRP. CONCLUSIONS: The results indicate that adenosine agonists inhibit spinal sensory transmission related to nociception by acting at the A1 receptors. The A1 receptor also seems to be involved in transmission related to the spinal motor system. Feedback inhibition mediated by GABA(A) receptors does not contribute to this antinociceptive action.
BACKGROUND:Adenosine analogs have been shown to produce antinociception after intrathecal administration. To determine the adenosine receptor subtype involved in spinal antinociception, the effects of selective agonists and an antagonist on the evoked potentials recorded from a neonatal rat spinal cord were studied. The measured potentials are a slow ventral root potential (slow VRP), which is the C-fiber-evoked excitatory response associated with nociceptive information; a monosynaptic reflex (MSR), which reflects a non-nociceptive transmission related to motor function; and a dorsal root potential (DRP), which reflects a gamma-aminobutyric acidA (GABA(A)) receptor-mediated presynaptic inhibition associated with analgesia. METHODS: The evoked potentials were recorded in response to electric stimulation of a lumbar dorsal root. Dose-response curves of agonists for these responses were obtained to determine their relative potency order. The antagonist dissociation constants (K(D) values) were estimated by Schild analysis. RESULTS:Adenosine agonists dose dependently inhibited the slow VRP and the MSR. However, the slow VRP was five to eight times more sensitive to them than was the MSR. The rank order of agonist potency was N6-cyclohexyladenosine (CHA) = N6-(R)-phenylisopropyladenosine (R-PIA) > 5'-N-ethylcarboxamidoadenosine (NECA) >> CGS 21680 in both responses. 8-Cyclopentyltheophylline produced dose-dependent parallel shifts to the right of NECA dose-response curves for these responses. Schild analysis gave linear plots with slopes near unity. The K(D) values of CPT for the MSR and the slow VRP were estimated to be 5.5 nM and 4.3 nM, respectively. The DRP was also depressed by adenosine agonists with potency order of CHA > NECA >> CGS 21680. 8-Cyclopentyltheophylline antagonized the inhibitory effects of CHA on the DRP. CONCLUSIONS: The results indicate that adenosine agonists inhibit spinal sensory transmission related to nociception by acting at the A1 receptors. The A1 receptor also seems to be involved in transmission related to the spinal motor system. Feedback inhibition mediated by GABA(A) receptors does not contribute to this antinociceptive action.
Authors: Christopher J Draper-Joyce; Rebecca Bhola; Jinan Wang; Apurba Bhattarai; Anh T N Nguyen; India Cowie-Kent; Kelly O'Sullivan; Ling Yeong Chia; Hariprasad Venugopal; Celine Valant; David M Thal; Denise Wootten; Nicolas Panel; Jens Carlsson; Macdonald J Christie; Paul J White; Peter Scammells; Lauren T May; Patrick M Sexton; Radostin Danev; Yinglong Miao; Alisa Glukhova; Wendy L Imlach; Arthur Christopoulos Journal: Nature Date: 2021-09-08 Impact factor: 49.962