Abstract: The transforming growth factor-? (TGF-?) superfamily is a multifunctional, contextually acting family of cytokines that participate in the regulation of development, disease and tissue repair in the nervous system. The TGF-? family is composed of several members, including TGF-?s, bone morphogenetic proteins (BMPs) and activins. In this review, we discuss recent findings that suggest TGF-? function as important pleiotropic modulators of nociceptive processing both physiologically and under pathological painful conditions. The strategy of increasing TGF-? signaling by deleting ?BMP and activin membrane-bound inhibitor? (BAMBI), a TGF-? pseudoreceptor, has demonstrated the inhibitory role of TGF-? signaling pathways in normal nociception and in inflammatory and neuropathic pain models. In particular, strong evidence suggests that TGF-?1 is a relevant mediator of nociception and has protective effects against the development of chronic neuropathic pain by inhibiting the neuroimmune responses of neurons and glia and promoting the expression of endogenous opioids within the spinal cord. In the peripheral nervous system, activins and BMPs function as target-derived differentiation factors that determine and maintain the phenotypic identity and circuit assembly of peptidergic nociceptors. In this context, activin is involved in the complex events of neuroinflammation that modulate the expression of pain during wound healing. These findings have provided new insights into the physiopathology of nociception. Moreover, specific members of the TGF-? family and their signaling effectors and modulator molecules may be promising molecular targets for novel therapeutic agents for pain management.

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