This article explores the role of brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin crucial for neuronal survival and plasticity, has gained attention for its potential as a modulator of synaptic transmission. The review delves into the molecular mechanisms underlying BDNF's involvement in pain processing and discusses its therapeutic potential in managing pain. It highlights recent advancements and challenges in translating BDNF-related research into clinical practice. BDNF is synthesized as proBDNF, which is proteolytically cleaved to form mature BDNF. Both forms can be released by neurons and initiate intracellular signaling pathways. Mature BDNF can induce long-term potentiation (LTP), while proBDNF sustains long-term depression (LTD) at synapses. BDNF's role in pain pathways involves its synthesis and release by various types of neurons and glia within pain pathways. Noxious stimuli can trigger BDNF production and release, leading to synaptic plasticity and increased responsiveness of peripheral nociceptors. The article also reviews the localization of BDNF in pain pathways, including primary sensory neurons (PSNs), second-order neurons (SSNs), and higher-order neurons. BDNF is expressed by PSNs in the dorsal root ganglia (DRGs) and cranial ganglia, as well as by SSNs in the spinal nucleus of the trigeminal nerve (SNTN) and nucleus tractus solitarius (NTS). Higher-order neurons in the brainstem, amygdala, and cerebral cortex also express BDNF. Neuronal mechanisms involving BDNF in nociceptive pathways focus on the synapses between PSNs and SSNs in the spinal cord. BDNF enhances glutamate release and modifies the function of AMPARs and NMDARs, leading to amplified nociceptive signals through LTP. BDNF exerts neuromodulatory effects under both normal and injured conditions, primarily functioning as a pro-nociceptive modulator in inflammatory, chronic, and neuropathic pain. Ex vivo studies on acute slices or slice organotypic cultures have shown that BDNF enhances the release of sensory neurotransmitters and excitatory responses to NMDA. In vivo studies on inflammatory pain have demonstrated that BDNF is an important pro-nociceptive modulator, enhancing glutamatergic transmission in the spinal dorsal horn through NMDAR plasticity. BDNF's role in pain pathways is complex and influenced by various factors, including cell type, molecular pathways, and pathological circumstances.This article explores the role of brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin crucial for neuronal survival and plasticity, has gained attention for its potential as a modulator of synaptic transmission. The review delves into the molecular mechanisms underlying BDNF's involvement in pain processing and discusses its therapeutic potential in managing pain. It highlights recent advancements and challenges in translating BDNF-related research into clinical practice. BDNF is synthesized as proBDNF, which is proteolytically cleaved to form mature BDNF. Both forms can be released by neurons and initiate intracellular signaling pathways. Mature BDNF can induce long-term potentiation (LTP), while proBDNF sustains long-term depression (LTD) at synapses. BDNF's role in pain pathways involves its synthesis and release by various types of neurons and glia within pain pathways. Noxious stimuli can trigger BDNF production and release, leading to synaptic plasticity and increased responsiveness of peripheral nociceptors. The article also reviews the localization of BDNF in pain pathways, including primary sensory neurons (PSNs), second-order neurons (SSNs), and higher-order neurons. BDNF is expressed by PSNs in the dorsal root ganglia (DRGs) and cranial ganglia, as well as by SSNs in the spinal nucleus of the trigeminal nerve (SNTN) and nucleus tractus solitarius (NTS). Higher-order neurons in the brainstem, amygdala, and cerebral cortex also express BDNF. Neuronal mechanisms involving BDNF in nociceptive pathways focus on the synapses between PSNs and SSNs in the spinal cord. BDNF enhances glutamate release and modifies the function of AMPARs and NMDARs, leading to amplified nociceptive signals through LTP. BDNF exerts neuromodulatory effects under both normal and injured conditions, primarily functioning as a pro-nociceptive modulator in inflammatory, chronic, and neuropathic pain. Ex vivo studies on acute slices or slice organotypic cultures have shown that BDNF enhances the release of sensory neurotransmitters and excitatory responses to NMDA. In vivo studies on inflammatory pain have demonstrated that BDNF is an important pro-nociceptive modulator, enhancing glutamatergic transmission in the spinal dorsal horn through NMDAR plasticity. BDNF's role in pain pathways is complex and influenced by various factors, including cell type, molecular pathways, and pathological circumstances.