Selective Cannabinoid CB₁ Receptor Activation Inhibits Spinal Nociceptive Transmission In Vivo

Abstract

Cannabinoid1 (CB1) receptors are located at CNS sites, including the spinal cord, involved in somatosensory processing. Analgesia is one of the tetrad of behaviors associated with cannabinoid agonists. Here, effects of a potent cannabinoid CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) on evoked responses of dorsal horn neurons in anesthetized rats were investigated. Extracellular recordings of convergent dorsal horn neurons were made in halothane anesthetized Sprague-Dawley rats (n = 16). Effects of spinal application of ACEA on electrically evoked responses of dorsal horn neurons were studied. Mean maximal effects of 0.5, 5, 50, and 500 ng/50 microl ACEA on the C-fiber-mediated postdischarge response were 79 +/- 6, 62 +/- 10, and 54 +/- 7% (P < 0.01), 45 +/- 6% (P < 0.01), of control, respectively. ACEA (500 ng/50 microl) also reduced the C-fiber-evoked nonpotentiated responses of neurons (59 +/- 9% of control, P < 0.05) and Adelta-fiber-evoked responses of neurons (68 +/- 10% of control, P < 0.01). Minor effects of ACEA on Abeta-fiber-evoked responses were observed. Spinal pre-administration of the selective CB1 receptor antagonist SR141716A (0.01 microg/50 microl) significantly reduced effects of ACEA (500 ng/50 microl) on postdischarge responses of dorsal horn neurons. This study demonstrates that spinal CB1 receptors modulate the transmission of C- and Adelta-fiber-evoked responses in anesthetized rats; this may reflect pre- and/or postsynaptic effects of cannabinoids on nociceptive transmission. CB1 receptors inhibit synaptic release of glutamate in rat dorsolateral striatum, a similar mechanism of action may underlie the effects of ACEA on noxious evoked responses of spinal neurons reported here.

Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia

“…These data are consistent with the presence of CB 1 receptors in the spinal dorsal horn (Tsou et al, 1998a;Hohmann et al, 1999a;Farquhar-Smith et al, 2000). Intrathecally-administered cannabinoids also produce antinociception (Yaksh, 1981;Smith and Martin, 1992;Welch and Stevens, 1992;Welch et al, 1995;Martin et al, 1999) and suppress noxious stimulus-evoked neuronal activity in spinal nociceptive neurons (Hohmann et al, 1998(Hohmann et al, , 1999bDrew et al, 2000;Kelly and Chapman, 2001), suggesting a functional role for spinal cannabinoid receptors in modulating nociceptive processing. Intrathecal administration of either rimonabant or CB 1 antisense oligonucleotides also elicits hyperalgesia (Richardson et al, 1998), suggesting that endocannabinoids may act tonically to suppress nociceptive responding.…”

Modulation of pain transmission by G-protein-coupled receptors

“…The CB1 receptor agonist ACEA inhibits C-fiber-evoked responses in spinal dorsal horn neurons in normal and inflammatory pain models (Kelly and Chapman, 2001;Khasabova et al, 2004). Spinal administration of the non-selective cannabinoid receptor agonist HU210 reduces the C-fiber mediated response of spinal dorsal horn neurons only in spinal nerveinjured rats (Kelly and Chapman, 2001).…”

“…Spinal administration of the non-selective cannabinoid receptor agonist HU210 reduces the C-fiber mediated response of spinal dorsal horn neurons only in spinal nerveinjured rats (Kelly and Chapman, 2001). However, for reducing Aδ-fiber-evoked responses, HU210 is effective in both sham-operated and nerve-injured rats (Chapman, 2001).…”

Endocannabinoid mechanisms of pain modulation

“…[82][83][84][85][86][87][88][89][90] Walker ' s laboratory fi rst demonstrated that cannabinoids suppress noxious stimulus -evoked neuronal activity in nociceptive neurons in the spinal cord and thalamus. 84 , 85 , 88 , 91 , 92 This suppression is observed in nociceptive neurons, generalizes to different modalities of noxious stimulation (mechanical, thermal, chemical), is mediated by cannabinoid receptors, and correlates with the antinociceptive effects of cannabinoids.…”