TGF-β and Opioid Receptor Signaling Crosstalk Results in Improvement of Endogenous and Exogenous Opioid Analgesia under Pathological Pain Conditions

Abstract

Transforming growth factor-␤1 (TGF-␤1) protects against neuroinflammatory events underlying neuropathic pain. TGF-␤ signaling enhancement is a phenotypic characteristic of mice lacking the TGF-␤ pseudoreceptor BAMBI (BMP and activin membrane-bound inhibitor), which leads to an increased synaptic release of opioid peptides and to a naloxone-reversible hypoalgesic/antiallodynic phenotype. Herein, we investigated the following: (1) the effects of BAMBI deficiency on opioid receptor expression, functional efficacy, and analgesic responses to endogenous and exogenous opioids; and (2) the involvement of the opioid system in the antiallodynic effect of TGF-␤1. BAMBI-KO mice were subjected to neuropathic pain by sciatic nerve crash injury (SNI). Gene (PCR) and protein (Western blot) expressions of -and ␦-opioid receptors were determined in the spinal cord. The inhibitory effects of agonists on the adenylyl cyclase pathway were investigated. Two weeks after SNI, wild-type mice developed mechanical allodynia and the functionality of -opioid receptors was reduced. By this time, BAMBI-KO mice were protected against allodynia and exhibited increased expression and function of opioid receptors. Four weeks after SNI, when mice of both genotypes had developed neuropathic pain, the analgesic responses induced by morphine and RB101 (an inhibitor of enkephalin-degrading enzymes, which increases the synaptic levels of enkephalins) were enhanced in BAMBI-KO mice. Similar results were obtained in the formalin-induced chemical-inflammatory pain model. Subcutaneous TGF-␤1 infusion prevented pain development after SNI. The antiallodynic effect of TGF-␤1 was naloxone-sensitive. In conclusion, modulation of the endogenous opioid system by TGF-␤ signaling improves the analgesic effectiveness of exogenous and endogenous opioids under pathological pain conditions.

T-Cell Mediation of Pregnancy Analgesia Affecting Chronic Pain in Mice

“…Gintzler and colleagues, in a series of studies in the rat, have established the importance of pregnancy-relevant gonadal hormones and spinal cord opioid receptors in producing pregnancy analgesia (Gintzler and Liu, 2001). Iwasaki et al (1991) also observed naloxone-reversible analgesia in the late stages of pregnancy in the colorectal distension, tail-flick, and hot-plate tests. Jayaram et al (1995Jayaram et al ( , 1997, working in mice, provided evidence for enkephalin mediation of pregnancy analgesia with the observation that the enkephalinase inhibitors SCH 32615 and RB 101 enhance the phenomenon.…”

“…The bulk of the pregnancy analgesia literature was compiled before it was widely recognized that neurons are not the only cell type processing pain; cells of the immune system such as microglia, macrophages, and T cells are now known to perform important signaling roles (Beggs and Salter, 2010;Grace et al, 2014;McMahon et al, 2015;. We recently demonstrated that females are likely using adaptive immune cells, T cells, to produce pain hypersensitivity after injury, whereas males use microglia to achieve the same ends (Sorge et al, 2015).…”

MicroRNA-30c-5p modulates neuropathic pain in rodents

“…Here, we have exploited the antiallodynic phenotype of mice lacking the TGF-b decoy receptor BAMBI (25,28,29) to identify potentially relevant miRNAs involved in neuropathic pain establishment. Next-generation sequencing and qPCR showed that miR-30c-5p was up-regulated in the SDH of neuropathic WT mice but remained unchanged in allodyniaresistant BAMBI −/− mice.…”

“…The antiallodynic effect of miR-30c-5p inhibitor involves the endogenous opioid system We have previously demonstrated that the TGF-b-dependent antiallodynic effect in mice depends on an increased activity of the endogenous opioid system (28,29). Therefore, we postulated that the antiallodynic effect of miR-30c-5p was mediated by endogenous opioids.…”

Micro ARN: ¿una nueva vía para el manejo del dolor neuropático?

“…La función biológica de este ARN de pequeño tamaño es inhibir la expresión del factor de crecimiento transformante β1 (o TGF-β1, de sus siglas en inglés) (7). Esta última molécula juega un papel relevante frenando la hipersensibilidad sensorial que acompaña a la lesión nerviosa (8). Por lo tanto, los autores sugieren que el incremento en la producción del miR-30c-5p podría estar relacionado con los síntomas neuropáticos de los roedores, a través de la disminución de las acciones del TGF-β1.…”