Evidence for a novel functional role of cannabinoid CB₂ receptors in the thalamus of neuropathic rats

Abstract

Cannabinoid CB 1 receptors have analgesic effects in models of neuropathic pain, but can also produce psychoactive side-effects. A supraspinal location of CB 2 receptors has recently been described. CB 2 agonists are also antinociceptive, although the functional role of supraspinal CB 2 receptors in the control of nociception is unknown. Herein, we provide evidence that CB 2 receptors in the thalamus play a functional role in the modulation of responses of neurons in the ventral posterior nucleus (VPL) of the thalamus in neuropathic, but not sham-operated, rats. Spontaneous and mechanically evoked activity of VPL neurons was recorded with a multichannel electrode array in anaesthetized spinal nerve-ligated (SNL) rats and compared to sham-operated rats. Intra-VPL administration of the CB 2 agonist JWH-133 (30 ng in 500 nL) significantly reduced spontaneous (P < 0.05), non-noxious (P < 0.001) and noxious (P < 0.01) mechanically evoked responses of VPL neurons in SNL rats, but not in sham-operated rats. Inhibitory effects of JWH-133 on spontaneous (P < 0.01) and noxious-evoked (P < 0.001) responses of neurons were blocked by the CB 2 antagonist SR144528. Local administration of SR144528 alone did not alter spontaneous or evoked responses of VPL neurons, but increased burst activity of VPL neurons in SNL rats. There were, however, no differences in levels of the endocannabinoids anandamide and 2AG in the thalamus of SNL and sham-operated rats. These data suggest that supraspinal CB 2 receptors in the thalamus may contribute to the modulation of neuropathic pain responses.

Gracile Neurons Contribute to the Maintenance of Neuropathic Pain in Peripheral and Central Neuropathic Models

“…1,4 In addition, we and others have reported that hemisection results in bilateral hyperexcitability of the thalamic VPL neurons, whereas SNL produces hyperexcitability in the contralateral side of the thalamic VPL neurons. 12,13 The present study, combined with previous results, suggests that spinal hemisection produces bilateral neuropathic pain, whereas spinal nerve ligation produces unilateral neuropathic pain that runs through pathways including the spinal dorsal horn neurons, gracile neurons, and thalamic VPL neurons.…”

“…We and others have reported that hyperexcitability of the thalamic VPL neurons contributes to mechanical allodynia in the hindpaw, which includes similar mechanisms of neuropathic pain in the spinal dorsal horn. 12,13 In contrast to STTs, DC-MLs mediate non-noxious inputs to the supraspinal site of the gracile nucleus, and is considered an important ascending pathway for mechanical allodynia. However, the contribution of gracile neurons to the neuropathic pain seen with peripheral and spinal cord injuries remains unclear.…”

Acute Resistance Exercise Induces Antinociception by Activation of the Endocannabinoid System in Rats

“…40 Others studies also confirmed the involvement of CB 2 receptors in the control of nociception at the spinal level. 41,42 However, at the supraspinal level only one study reported that noxious mechanically evoked responses in neurons of the ventral posterior nucleus of the thalamus, 43 a site that modulates pain processing, 44 was reduced in spinal nerve-ligated rats by intrathalamic administration of the selective CB 2 cannabinoid receptor agonist JWH133. This effect was blocked by the CB 2 cannabinoid receptor antagonist SR144528, suggesting the involvement of CB 2 receptors in the control of noxious stimuli in this brain area.…”

Palmitoylethanolamide Protects Dentate Gyrus Granule Cells via Peroxisome Proliferator-Activated Receptor-Alpha

“…For example, it was shown that PEA selectively activates PPAR-alpha with an EC 50 of 3.1 lM in vitro and lost its anti-inflammatory properties in PPAR-alpha deficient mice (Lo Verme et al 2005a). Data obtained from a model of inflammatory hyperalgesia underline the contribution of PPAR-alpha activation to PEA-mediated anti-inflammatory effects since after intraplantar injection of carrageenan PEA lowered inflammatory pain and this effect was blocked by the PPAR-alpha antagonist GW6471 (Jhaveri et al 2008). PPAR-alpha activation by other agonists than PEA, for example by the specific synthetic agonist Wy-14,643, is known to suppress inflammatory mechanisms in various models of multiple sclerosis (Heneka and Landreth 2007).…”