Acute, physiological pain serves as an important warning signal in our body to avoid dangerous stimuli or environment, manifesting as a high activation threshold and short duration. It is like the pain we usually experience in response to a needle prick or a flame. Our bodies need to have this type of pain because it can help to protect us from the danger. Physiological pain is triggered by specialized sensory nociceptors innervating peripheral tissues such as skin, gland etc. The nociceptive sensory signals generated by nociceptors then leads to activation of secondary neurons in the spinal cord, which further project to the cortex via a relay in the thalamus, eliciting acute pain response (Fig. 1). However, this acute pain can persist and turn into chronic pain under various pathological states induced by long-lasting tissue damage or nerve injury via trauma, metabolic disorders, pathogenic infections, or tumor growth (Ji, Chamessian, & Zhang, 2016; Kong et al., 2021; Wu, Zhu, & Gao, 2021). Unlike acute, physiological pain, chronic, pathological pain often manifests as a lowered threshold and sustained pain hypersensitivity lasting for weeks, months or even years. It consists of spontaneous pain (pain experience in the absence of external stimulus), hyperalgesia (an increased pain sensitivity to a noxious stimulus) and allodynia (an abnormal pain in response to a normally non-noxious stimulus) (Fig. 1). Plasticity in a large numbers of brain regions from the periphery to central nervous system leads to peripheral and central sensitization, which ultimately contribute to pain chronicity in a multidimensional manner (Ji, 2022; Kuner & Kuner, 2021).

Chronic pain is a major global healthcare issue. It exerts a serious impact on an individual's life and social activities, bringing heavy burden to the families and society (Global Burden of Disease Study, C, 2015). Moreover, chronic pain is frequently comorbid with anxiety, depression, fear, sleep disorders, etc., rendering it more intractable (Bair, Robinson, Katon, & Kroenke, 2003; Campbell & Meyer, 2006; McWilliams, Goodwin, & Cox, 2004; Simon, VonKorff, Piccinelli, Fullerton, & Ormel, 1999; Yan, Mo, Ha, & Deng, 2022). Despite the fact that much progress has been made in understanding the mechanisms of chronic pain, optimal therapies for pain relief have been far from developed for several decades. So far, the non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are still the backbone of analgesics in clinic, both of which are associated with unwanted central side effects, e.g. inadequate analgesic efficacy, analgesic tolerance, drug abuse, respiratory inhibition, etc. (Ashburn & Fleisher, 2018; Busse et al., 2018; Corder et al., 2017; Roeckel, Le Coz, Gaveriaux-Ruff, & Simonin, 2016; Stoicea et al., 2019; Vandenberg, Ryan, Carland, Imlach, & Christie, 2014; Weisberg, Becker, Fiellin, & Stannard, 2014). Thus, it is very urgent to explore in depth mechanisms of chronic pain and a major challenge to devise new therapeutic strategies for pain relief with least side effects.

Glutamate is the primary neurotransmitter to mediate excitatory synaptic responses in the nociceptive pathways, which exerts its excitatory effect via ionotropic or metabotropic glutamate receptors (Fig. 2) (Hansen et al., 2021). Under physiological states (everyday painful events), synaptically released glutamate predominantly acts on two types of ionotropic glutamate receptors, namely α-amino-3-hydroxy-5-methyl-4-isoxalepropionate receptors (AMPARs) and kainate receptors (KARs) to elicit fast excitatory synaptic transmission throughout the somatosensory nociceptive pathways, i.e. spinal dorsal horn (Li et al., 1999; Yoshimura & Jessell, 1990), thalamus (Blomqvist, Ericson, Craig, & Broman, 1996), somatosensory cortex (Kidd & Isaac, 1999), ACC (Wu, Ko, & Zhuo, 2007; Wu, Zhao, Toyoda, Ko, & Zhuo, 2005), amygdala (Li & Rogawski, 1998; Neugebauer, Li, Bird, Bhave, & Gereau, 2003; Ren & Neugebauer, 2010), insula (Liu et al., 2013; Liu et al., 2013), etc. Glutamate also binds to NMDA receptors, but this is normally of no functional consequence because NMDA receptors exhibit voltage-dependent Mg2+ block. However, under pathological states (e.g. injury or inflammation), sustained activation of AMPA and KA receptors by maintained release of glutamate causes strong depolarization of postsynaptic neurons so that NMDA receptors is relieved from Mg2+ blockade and gets activated, mediating a slow excitatory synaptic response (Mayer, Westbrook, & Guthrie, 1984). In addition to the above ionotropic glutamate receptors (iGluRs), glutamate can also act on metabotropic (G-protein coupled receptors) receptors. When glutamate binds metabotropic glutamate receptors (mGluRs), it activates intracellular signaling pathways via interaction with different G proteins (Niswender & Conn, 2010).

Glutamate receptors are traditionally thought to be localized on the postsynaptic side, and the existence and functional roles of such receptors on the presynaptic side of the synapse have been less well studied. Compelling evidence from anatomical and physiological results demonstrates the presence of presynaptic glutamate receptors in various brain regions, i.e. somatosensory cortex (Brasier & Feldman, 2008), hippocampus (McGuinness et al., 2010), visual cortex (Buchanan et al., 2012), cerebellum (Duguid & Smart, 2004), amygdala (Humeau, Shaban, Bissière, & Lüthi, 2003), corticostriatal synapses (Park, Popescu, & Poo, 2014), and spinal primary afferent terminals (Liu et al., 1994). These presynaptic glutamate receptors have been implicated in shaping synaptic transmission and plasticity (Abrahamsson et al., 2017; Banerjee, Larsen, Philpot, & Paulsen, 2016; Bardoni, 2013; Humeau et al., 2003; Park et al., 2014; Reiner & Levitz, 2018; Sjöström, Turrigiano, & Nelson, 2003; Zanetti, Regoni, Ratti, Valtorta, & Sassone, 2021). Although a role for presynaptic glutamate receptors in neurotransmitter release was first suggested decades ago, important questions still remain regarding the synapse-specific expression and functions of presynaptic glutamate receptors in the nociceptive pathways. In this review, we'll focus on reviewing the expression of presynaptic glutamate receptors in the nociceptive pathways and their crucial functions in nociception. We uncover the cellular and molecular mechanisms of presynaptic glutamate receptors in shaping synaptic transmission and plasticity to mediate pain chronicity, which may provide therapeutic approaches for the treatment of chronic pain.