Cannabinoid CB₂ receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain

Abstract

Peripheral cannabinoid 2 receptors (CB2 receptors) modulate immune responses and attenuate nociceptive behaviour in models of acute and persistent pain. The aim of the present study was to investigate whether peripheral CB2 receptors modulate spinal processing of innocuous and noxious responses and to determine whether there are altered roles of CB2 receptors in models of persistent pain. Effects of local administration of the CB2 receptor agonist JWH-133 (5 and 15 microg/50 microL) on mechanically evoked responses of spinal wide dynamic range (WDR) neurons in noninflamed rats, rats with carrageenan-induced hindpaw inflammation, sham operated rats and spinal nerve-ligated (SNL) rats were determined in anaesthetized rats in vivo. Mechanical stimulation (von Frey filaments, 6-80 g) of the peripheral receptive field evoked firing of WDR neurons. Mechanically evoked responses of WDR neurons were similar in noninflamed, carrageenan-inflamed, sham-operated and SNL rats. Intraplantar injection of JWH-133 (15 microg), but not vehicle, significantly (P < 0.05) inhibited innocuous and noxious mechanically evoked responses of WDR neurons in all four groups of rats. In many cases the selective CB2 receptor antagonist, SR144528 (10 microg/50 microL), attenuated the inhibitory effects of JWH-133 (15 microg) on mechanically evoked WDR neuronal responses. The CB1 receptor antagonist, SR141716A, did not attenuate the inhibitory effects of JWH-133 on these responses. Intraplantar preadministration of JWH-133 also inhibited (P < 0.05) carrageenan-induced expansion of peripheral receptive fields of WDR dorsal horn neurons. This study demonstrates that activation of peripheral CB2 receptors attenuates both innocuous- and noxious-evoked responses of WDR neurons in models of acute, inflammatory and neuropathic pain.

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

“…This inhibitory effect was reversed by pharmacologic blockade of CB 2 Rs (AM630) or was absent in CB 2 −/− mice, suggesting a CB 2 R-mediated effect. This finding is consistent with previous reports in which JWH133 or other CB 2 R agonists inhibited spontaneous and evoked neuronal firing to noxious stimuli in spinal cord and thalamus (44)(45)(46)(47) and inhibited excitatory neuronal firing in the prefrontal cortex (48). Thus, our electrophysiological data provide direct evidence demonstrating that the expressed CB 2 Rs in VTA DA neurons are functional, and that activation of these receptors inhibits VTA DA neuronal firing and decreases VTA DA neuronal excitability.…”

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

“…In contrast, a 10 g stimulation of the contralateral hindpaw did not evoke a significant paw withdrawal in SNL or sham-operated rats (data not shown). Thus SNL rats developed marked mechanical allodynia after tight ligation of L5 and L6 nerves, which is in agreement with previous studies of this model (Kim and Chung, 1992;Chapman et al, 1998;Elmes et al, 2004;Jhaveri et al, 2005).…”

“…Activation of both the cannabinoid 1 receptor (CB 1 ) and CB 2 reduces nociceptive processing in animal models of neuropathic pain (Hohmann, 2002;Howlett et al, 2002;Elmes et al, 2004;Sagar et al, 2005). Furthermore, nociceptive processing is tonically modulated by the endocannabinoids.…”

AM404, an anandamide transport inhibitor, reduces plasma extravasation in a model of neuropathic pain in rat: Role for cannabinoid receptors

“…A strong recruitment of these cells at the ligation site participates in the subsequent neurogenic inflammation evoked by CCI of sciatic nerve (Moalem and Tracey, 2006). Thus, the stimulation of peripheral CB2 receptors (Elmes et al, 2004) could result in the inhibition of the sensitizing substances that leads to reduction of pain threshold and vascular active neurokinins.…”