Functional supra-spinal CB2 receptors in neuropathic model of pain

Maulik Jhaveri, Clare Spicer, David Kendall, Victoria Chapman
University of Nottingham, Nottingham, United Kingdom

There is growing evidence for the presence of cannabinoid CB2 receptors in the CNS in addition to the periphery (Van Sickle et al., 2005; Gong et al., 2006). In neuropathic states, CB2 receptors are up-regulated in the spinal cord and their activation attenuates evoked responses of spinal neurones (Sagar et al., 2005). The role of supraspinal CB2 receptors in neuropathic pain states is unknown. The aim of this study was to investigate whether activation of supraspinal CB2 receptors modulates neuropathic pain behaviour.

Spinal nerves L5 and L6 of male Sprague-Dawley rats (100-125 g) were tightly ligated to induce peripheral mononeuropathy. An intracerebral guide cannula was stereotaxically implanted for injection into the ventral posterolateral (VPL) nucleus of the thalamus or the, basolateral amygdala (BLA) and lateral ventricle, 7-8 days following spinal nerve ligation (SNL). Fourteen to eighteen days post-SNL surgery, effects of intracerebral or intracerebroventricular (icv) injection of the opioid morphine, the cannabinoid agonist CP55940 and the selective CB2 receptor agonist JWH133 on mechanical paw withdrawal threshold, a measure of mechanical allodynia, were studied. Data were analysed using one-way ANOVA followed by Bonferroni’s multiple comparison test.

In SNL rats, mechanical paw withdrawal threshold was significantly (P < 0.001, n = 26) reduced in the nerve-injured hindpaw (2.2 ± 0.2 g), compared to the contralateral paw (14.4 ± 0.4g). Intra-VPL injection of morphine (20 μg in 500 nl) increased (P < 0.01, n = 3) paw withdrawal thresholds at 15 min and 60 min (12 ± 3 g vs 2 ± 1 g) post-injection compared to saline controls. Intra-VPL injection of JWH133 (46 ng in 500 nl) did not alter paw withdrawal threshold (P > 0.05, n = 5-8), compared to vehicle controls. In contrast, intra-BLA injection of JWH133 (46 ng in 500 nl) increased (P < 0.05, n = 6) ipsilateral paw withdrawal threshold at 15 min post-injection (9.2 ± 1.4 g vs 3.3 ± 0.4 g), compared to pre-injection baseline values. ICV injection of CP55940 (40 μg in 1 μl 60% DMSO), but not JWH133 (40 μg in 1 μl), significantly (P < 0.05, n = 7) attenuated changes in paw withdrawal threshold at 15 min post-injection (7.1 ± 2.2 vs 1.5 ± 0.3 g) compared to pre-injection values.

These data indicate that cannabinoid CB2 receptors in the BLA, but not the VPL or periventricular brain regions, may be able to modulate nociceptive processes in neuropathic pain. Our data suggest that further studies are required to elucidate fully the potential central sites of action of cannabinoid ligands acting at CB2 receptors.

Gong et al., 2006, Brain Res 1, 10-23
Sagar et al., 2005, Eur J Neurosci 22, 371-379
Van Sickle et al., 2005, Science 310, 329-332