Differential Effects of CB1 and Opioid Agonists on Two Populations of Adult Rat Dorsal Root Ganglion Neurons

Nerve Growth Factor (NGF) Regulates Activity of Nuclear Factor of Activated T-cells (NFAT) in Neurons via the Phosphatidylinositol 3-Kinase (PI3K)-Akt-Glycogen Synthase Kinase 3β (GSK3β) Pathway

“…However, the amplitudes of these [Ca 2ϩ ] i fluctuations were rather small (Ͻ50 nM) and below the [Ca 2ϩ ] i levels required to activate NFAT in DRG neurons (200 -300 nM) (7). In contrast, we and others observed no evidence of [Ca 2ϩ ] i fluctuations under resting conditions in the majority of DRG neurons cultured either with or without NGF (7,30,41,(62)(63)(64)(65)(66)(67)(68)(69). One possible explanation for these differences is that the study by Ozaki et al (61) used cells that had been maintained in culture for an extended period prior to the experimentation (4 -14 days) and also a relatively high concentration of NGF (100 ng/ml).…”

The cannabinoid receptor agonist, WIN 55, 212-2, attenuates tumor-evoked hyperalgesia through peripheral mechanisms

“…Additionally, intraplantar administration of the selective CB 1 agonist, arachidonyl-2-chloroethylamide (ACEA), attenuated mechanically-evoked responses of nociceptive spinal cord neurons following carrageenan inflammation, which was also likely due to activation of CB 1 receptors on nociceptors (Kelly et al, 2003). Further support for that mechanism of action is suggested by previous studies showing that activation of CB 1 receptors can decrease highvoltage activated calcium currents (Ross et al, 2001;Khasabova et al, 2002Khasabova et al, , 2004 and reduce capsaicin-evoked calcium transients (Millns et al, 2001;Sagar et al, 2005) in nociceptive dorsal root ganglion neurons. It is likely that activation of CB 1 receptors on nociceptive primary afferent fibers is responsible for the decrease in tumor-evoked mechanical hyperalgesia in our study.…”

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…A prominent example is the inhibition of substance P and calcitonin gene-related peptide (CGRP) release (both are pronociceptive and proinflammatory neuropeptides) from central and peripheral terminals of primary afferent neurons ( Fig. 1) (Yaksh, 1988;Khasabova et al, 2004;Kondo et al, 2005). At the postsynaptic membrane, opioid receptors mediate hyperpolarization by opening G protein-coupled inwardly rectifying K ϩ (GIRK) channels, thereby preventing neuronal excitation and/or propagation of action potentials for review, see Lü scher and Slesinger, 2010).…”

“…Opioid receptors are transported to the peripheral nerve terminals Li et al, 1996;Puehler et al, 2004;Mousa et al, 2007a) and couple to G i/o proteins that inhibit adenylyl cyclases and modulate ion channels (Zöllner et al, 2003;Zöllner et al, 2008). The inhibition of Ca 2ϩ channels seems to be a major mechanism for the opioid-induced suppression of DRG neuron functions (Akins and McCleskey, 1993;Acosta and López, 1999;Khasabova et al, 2004;Wang et al, 2010). Interactions between different opioid receptor types, possibly via heterodimerization, can facilitate coupling to Ca 2ϩ channels (Walwyn et al, 2005(Walwyn et al, , 2009).…”

“…Specifically, it was shown that a lack of ␤-arrestin2 reduced the inhibition of voltage-dependent Ca 2ϩ channels by -agonists, diminished constitutive recycling, and increased cell-surface localization of -receptors in DRG neurons (Walwyn et al, 2007). In summary, opioid agonists can attenuate the excitability of primary afferent neurons and block the release of proinflammatory neuropeptides (substance P, CGRP) from central and peripheral terminals (Junger et al, 2002;Stein et al, 2003;Khasabova et al, 2004). Particularly within injured tissue, these events led to antinociceptive and anti-inflammatory effects (see sections II.A.5 and II.C).…”