Rapid pain modulation with nuclear receptor ligands

Abstract

We discuss and present new data regarding the physiological and molecular mechanisms of nuclear receptor activation in pain control, with a particular emphasis on non-genomic effects of ligands at peroxisome proliferator-activated receptor (PPAR), GPR30, and classical estrogen receptors. PPARalpha agonists rapidly reduce both acute and chronic pain in a number of pain assays. These effects precede transcriptional anti-inflammatory actions, and are mediated in part by IK(ca) and BK(ca) channels on DRG neurons. In contrast to the peripheral site of action of PPARalpha ligands, the dorsal horn supports the expression of PPARgamma. Intrathecal administration of PPARgamma ligands rapidly (< or =5 min) attenuated mechanical and thermal hypersensitivity associated with nerve injury in a dose-dependent manner that could be blocked with PPARgamma antagonists. By contrast, a PPARgamma antagonist itself rapidly increased the mechanical allodynia associated with nerve injury. These data suggest that ligand-dependent, non-genomic activation of spinal PPARgamma decreases behavioral signs of inflammatory and neuropathic pain. We also report that the GPR30 is expressed on cultured sensory neurons, that activation of the receptor elicits signaling to increase calcium accumulation. This signaling may contribute to increased neuronal sensitivity as treatment with the GPR30 agonist induces hyperalgesia. Finally, application of the membrane-impermeable 17beta-E(2)-BSA rapidly (within 15 min) enhanced BK-stimulated inositol phosphate (IP) accumulation and PGE(2)-mediated cAMP accumulation in trigeminal ganglion cultures. We conclude that nuclear receptor ligands may operate through rapid, non-genomic mechanisms to modulate inflammatory and neuropathic pain.

Figure 1. PPARγ tonically inhibits neuropathic pain

Intrathecal administration of BADGE (200 μg, n=8) but not DMSO vehicle (n=4) enhanced the drop in VF threshold associated with spared nerve injury. F(1,70)=24, p<0.001 by 2-way ANOVA. *p<0.05 by post-hoc tests. Error bars represent SEM. Contributed by B. Taylor.

Figure 2. Neuronal expression (indicated by N52 staining, blue) of the GPR30 receptor (green) in trigeminal ganglia cultures derived from female rats

Arrows highlight GPR30-positive neurons which colocalize with TRPV1 (red). Contributed by Fehrenbacher and Hargreaves.

Figure 3. G-1 (100nM) increases the intracellular concentration of calcium in female TG neurons in culture

A. Time course of G-1-induced increases in calcium. All cells received the same treatment, but only those indicated by red (n=54) were responsive to G-1. In B, the average basal Ca²⁺_i was subtracted from the peak Ca²⁺_i to determine the extent of calcium mobilization by G-1 in both responsive and non-responsive cells. An asterisk indicates significant differences between responsive and non-responsive cells; p<0.0001 using t-test. Contributed by Fehrenbacher and Hargreaves.

Figure 4. The effect of 17ß-E₂ on cellular responses to BK and PGE₂ in TG nociceptors in culture (A) and on the time-course of BK-induced thermal allodynia in vivo (B)

Data shown in (A) represent the mean ± SD of 2 experiments measuring total inositol phosphate (IP) accumulation in response to BK (1 μM) in the absence (DMSO vehicle) or presence of 17ß-estradiol. Data shown in (B) represents paw withdrawal latency to heat in response to bradykinin when tested 15 min after the injection of 17ß-estradiol (1 or 100 ng). Contributed by W. Clarke.