‘Knock-down’ of spinal CB1 receptors produces abnormal pain and elevates spinal dynorphin content in mice

Abstract

Recent studies demonstrate the possible existence of tonic modulatory control of nociceptive input mediated by spinal cannabinoid receptors (CB1). Accordingly, it is predicted that a reduction in the spinal CB1 receptors may enhance sensitivity to sensory stimuli and a decrease in spinal antinociceptive potency to cannabinoid agonists. An antisense oligodeoxynucleotide (ODN) specific to the CB1 receptor was used to 'knock-down' CB1 receptors in the lumbar spinal cord and dorsal root ganglia by the local, repeated intrathecal (i.th.) administration of the ODN. This treatment resulted in a decrease in lumbar spinal CB1 receptor expression accompanied by a decrease in the response thresholds to both innocuous tactile and noxious thermal stimuli. The antinociceptive action of the CB1 agonist, WIN 55,212-2, by i.th. administration was also significantly attenuated after treatment with the antisense ODN. Similar treatment using a mismatch control ODN had no effect on receptor protein or on sensory thresholds. The effects of the antisense ODN treatment on sensory thresholds were fully reversed after discontinuation of the ODN injection. The antisense ODN treated rats also showed a significant increase in lumbar spinal dynorphin A. Acute i.th. injection of MK-801 or an antidynorphin antiserum blocked the antisense ODN-induced tactile and thermal hypersensitivity. These data support the possibility of endogenous inhibitory cannabinoid tone to limit spinal afferent input of thermal and tactile stimuli. Lifting of this inhibitory tone through a 'knock-down' of spinal CB1 receptors apparently lowers the thresholds for sensory input, as reflected by the actions of MK-801 to block tactile and thermal hypersensitivity. The increased spinal dynorphin may act to further promote afferent outflow and abnormal pain because sequestration of spinal dynorphin with antiserum also reverses the manifestations of abnormal pain following knock-down of CB1 receptors.

Dual Regulation of Anterograde and Retrograde Transmission by Endocannabinoids

“…Several studies have demonstrated cross talk between the eCB and -opioid systems (Welch and Eads, 1999;Dogrul et al, 2002;Sáez-Cassanelli et al, 2007) in which activation of one receptor system alters the efficacy of the other. We have previously shown that dynorphin inhibits the EPSC via a presynaptic mechanism (Iremonger and Bains, 2009).…”

Modulation of pain transmission by G-protein-coupled receptors

“…Some studies suggest that endogenous cannabinoids are important for nociceptive regulation at the spinal and peripheral levels. For instance, intrathecal administration of the CB1 receptor antagonist SR141716A or antisense knockdown of spinal CB1 receptors produce thermal hyperalgesia (Richardson et al, 1998b;Dogrul et al, 2002). Spinal administration of SR141716A selectively facilitates the C-fiber-mediated nociceptive responses of dorsal horn neurons in rats (Chapman, 1999).…”

Cannabinoid receptor expression and phosphorylation are differentially regulated between male and female cerebellum and brain stem after repeated stress: Implication for PTSD and drug abuse

“…Further immunohistochemistry/in situ hybridization studies are required to determine specific changes in cannabinoid receptor expression in these nuclei after stress and their correlations with behavioral changes in PTSD models. Cannabinoid receptors expressed in the periaqueductal gray, locus coeruleus, raphe nuclei, reticular activating system, solitary tract, vestibular and cochlear nuclei of brain stem are thought to play important roles in the regulation of pain sensation, sleep-awake cycle, acoustic startle response, cardiovascular reactivity that are frequently altered in subjects with PTSD [1,2,12,[30][31][32]38,48].…”