GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

Role of Gangliosides in Peripheral Pain Mechanisms

Gangliosides are abundantly occurring sialylated glycosphingolipids serving diverse functions in the nervous system. Membrane-localized gangliosides are important components of lipid microdomains (rafts) which determine the distribution of and the interaction among specific membrane proteins. Different classes of gangliosides are expressed in nociceptive primary sensory neurons involved in the transmission of nerve impulses evoked by noxious mechanical, thermal, and chemical stimuli. Gangliosides, in particular GM1, have been shown to participate in the regulation of the function of ion channels, such as transient receptor potential vanilloid type 1 (TRPV1), a molecular integrator of noxious stimuli of distinct nature. Gangliosides may influence nociceptive functions through their association with lipid rafts participating in the organization of functional assemblies of specific nociceptive ion channels with neurotrophins, membrane receptors, and intracellular signaling pathways. Genetic and experimentally induced alterations in the expression and/or metabolism of distinct ganglioside species are involved in pathologies associated with nerve injuries, neuropathic, and inflammatory pain in both men and animals. Genetic and/or pharmacological manipulation of neuronal ganglioside expression, metabolism, and action may offer a novel approach to understanding and management of pain.

Toll-like receptor 2 plays an essential role in electroacupuncture analgesia in a mouse model of inflammatory pain

Background: Inflammatory pain occurs when local tissue injury activates macrophages and neutrophils, hence increasing pro-inflammatory cytokine and chemokine levels. Toll-like receptor 2 (TLR2) antagonism reportedly suppresses neuropathic and inflammatory pain. Aims: In the present study, we investigated the effect of electroacupuncture (EA) on TLR2 and related signalling molecules in a complete Freund’s adjuvant (CFA)-induced mouse model of inflammatory pain to determine whether EA can attenuate inflammatory pain via the TLR2 signalling pathway. Methods: EA significantly reduced mechanical and thermal hyperalgesia in the animal model. A similar effect was produced by TLR2 antagonism induced by CU-CPT22 injection. Results: TLR2 expression in the dorsal root ganglia, spinal cord and thalamus increased following induction of inflammation. Expression levels of downstream molecules such as pPI3K, pAkt and pmTOR also increased, as did those of MAPK subfamily members such as pERK, pp38 and pJNK. Transcription factors (pCREB and pNFκB) and nociceptive ion channels (Nav1.7 and Nav1.8) were also involved. Conclusion: Increased expression of the above molecules was attenuated by both EA and TLR2 antagonism. Our results show that EA attenuates inflammatory pain via TLR2 signalling.

Elevated Peritoneal Expression and Estrogen Regulation of Nociceptive Ion Channels in Endometriosis

Context: Ovarian suppression is a common treatment for endometriosis-associated pelvic pain. Its exact mechanism of action is poorly understood, although it is assumed to reflect reduced production/action of estrogens. Objective: The objective of the study was to measure the expression of mRNAs encoded by nociceptive genes in the peritoneum of women with chronic pelvic pain (CPP) with or without endometriosis and to investigate whether estrogens alter nociceptive gene expression in human sensory neurons. Design: The study was performed using human tissue analysis and cell culture. Setting: The study was conducted at a university research institute. Patients: Peritoneal biopsies were obtained from women with CPP and endometriosis (n = 12), CPP and no endometriosis (n = 10), and no pain or endometriosis (n = 5). Endometriosis lesions were obtained from women with endometriosis (n = 18). Main Outcome Measures: mRNAs encoding ion channels (P2RX3, SCN9A, SCN11A, TRPA1, TRPV1) and the neurotransmitter TAC1 were measured in human tissue samples and in human embryonic stem cell-derived sensory neurons treated with estrogens. Results: TRPV1, TRPA1, and SCN11A mRNAs were significantly higher in the peritoneum from women with endometriosis (P < .001, P < .01). TRPV1, SCN9A, and TAC1 were elevated in endometriosis lesions (P < .05). P2RX3 mRNA was increased in the peritoneum of women with CPP, with and without endometriosis (P < .05). Incubation of sensory neurons with 17β-estradiol increased TRPV1 mRNA (P < .01). The estrogen receptor-β-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile increased concentrations of TRPV1, P2RX3, SCN9A, and TAC1 mRNAs. Conclusions: Estrogen-dependent expression of TRPV1 in sensory neurons may explain why ovarian suppression can reduce endometriosis-associated pain. Strategies directly targeting ion channels may offer an alternative option for the management of CPP.