Glutamate pharmacology and metabolism in peripheral primary afferents: Physiological and pathophysiological mechanisms☆
Introduction
Peripheral afferent nerve terminals provide sensory innervation to skin, joint, fascia, muscle, bone, and viscera. In the role as sensory terminals, they transduce mechanical, thermal, and chemical stimuli to electrochemical information that is transmitted to the spinal cord and brainstem (Woolf & Ma, 2007). The current review will focus on the glutamatergic role of the peripheral sensory terminal based upon two important neuroscience concepts from the last half of the 20th century. Firstly, l-glutamate is a major excitatory neurotransmitter of the vertebrate nervous system including primary afferents (Johnson, 1972a, Johnson, 1972b), and secondly, some peripheral sensory terminals have efferent functions (Jancso et al., 1967). Although there is evidence for the role of glutamate in visceral peripheral afferents (McRoberts et al., 2001, Ghosh et al., 2007, Lindström et al., 2008), the focus of this review will concentrate on evidence of glutamate release from and influence on somatic peripheral afferents.
Section snippets
Primary afferents and efferent function
Primary afferent neurons are nerve cells that convey peripheral sensory information to the spinal cord and brainstem (Fig. 1). They possess a cell body located in the dorsal root ganglion (DRG) or trigeminal ganglion (TG) and an axonal fiber that projects from the periphery to the spinal cord or brainstem (Woolf & Ma, 2007). Primary afferent neurons can be classified into two broad functional categories. In one category, neurons convey proprioceptive, vibratory, or discriminative touch
Glutamate
Both the central and peripheral nervous systems (CNS and PNS) have a glutamine cycle for the production and degradation of glutamate as a neurotransmitter (Fig. 2; Miller et al., 2002, McKenna, 2007). A series of studies demonstrates a high concentration of glutamate in DRG, dorsal roots, and peripheral nerve (Porcellati and Thompson, 1957, Graham et al., 1965, Graham et al., 1967, Wheeler and Boyarsky, 1968, Duggan and Johnston, 1970a, Duggan and Johnston, 1970b, Johnson and Aprison, 1970a,
Stimulated release
The previous section indicated that the primary afferent cell body is a neuron that produces glutamate via particular biochemical pathways and that glutamate is packaged in synaptic vesicles via VGLUTs. Furthermore, evidence indicates that similar biochemical events occur in the peripheral axon, that glutamate is transported in peripheral nerve, and that there is mechanism for release, i.e., VGLUTs and vesicular release proteins (Fig. 5; Averill et al., 2004, Ibitokun and Miller, 2010a,
Excitatory amino acid receptors
Release of glutamate in the periphery would warrant the presence of EAARs for biological function (Fig. 5). DRG neuronal cell bodies synthesize a number of EAARs (Sato et al., 1993, Petralia et al., 1994a, Petralia et al., 1994b, Ohishi et al., 1995a, Ohishi et al., 1995b, Li et al., 1996, Kinoshita et al., 1998, Walker et al., 2001, Marvizónz et al., 2002) and one site of action for glutamate could be the peripheral primary afferent terminal. EAARs have been localized to primary afferents and
Ventral root potentials
The electrophysiological actions of glutamate and EAAR agonists first were studied indirectly by recording the ventral root potentials in an isolated spinal cord-tail preparation in neonatal rat. Nociceptive afferents in neonatal rat tail skin are activated by l-glutamate (ED50 = 136 μM) to produce nociceptive reflexes, but not d-glutamate or other l-amino acids (Ault and Hildebrand, 1993a, Ault and Hildebrand, 1993b, Ault and Hildebrand, 1993c). Peripheral application of kainate (10–300 μM) and
Peripheral effects of glutamate: biophysical
A large body of biophysical evidence demonstrates glutamate's numerous effects in the periphery. In the spinal cord, presynaptic regulation of glutamate release from primary afferent fibers involves activation of EAARs by glutamate (Kerchner et al., 2001, Huettner et al., 2002, Lee et al., 2002, Bardoni et al., 2004, Park et al., 2004) and a similar phenomenon may occur at the peripheral terminal (Table 2).
Peripheral effects of glutamate: animal behavior
Glutamate, released from nociceptors or exogenously applied, produces nociceptive actions in animals and painful responses in humans. Altered nociceptive behavior often is described in terms of response to mechanical and/or thermal stimulation. Increased response to a noxious mechanical or thermal stimulus is termed hyperalgesia, whereas a nociceptive response to a non-noxious stimulus is termed allodynia (Table 3).
Acute and chronic pain
Inflammatory pain involves numerous chemical agents that act directly as transducers or sensitizers on primary afferent terminal receptors or indirectly activate primary afferents by initiating an inflammatory cascade (Woolf & Ma, 2007). During inflammation, peripheral or primary sensitization of primary afferent fibers occurs with a lowering of nociceptive threshold and increased excitability. Central or secondary sensitization can occur at primary afferent synapses with elevated glutamate
Capsaicin
Capsaicin, TRPV1 agonist, produces thermal hyperalgesia when injected into the rat hindpaw (Turner et al., 2003, Carlton et al., 2009, Jin et al., 2009). Co-administration i.pl. of MK-801 (0.1–1.0 mM) or CNQX (1–5 mM) decreases capsaicin-induced (3.0 mM, 50 μl) thermal hyperalgesia (thermal plantar) in a dose dependent manner (Jin et al., 2009). This effect occurs within 15 min and lasts for more than 6 h. Co-treatment of mGluR1 or mGluR5 antagonists, CPCCOEt (5 mM) or MPEP (30 mM), dose dependently
Pain during acute inflammation: joint and muscle
Acute inflammation of the rat knee joint causes mechanical and thermal hyperalgesia in the hindpaw and altered weight-bearing (Sluka and Westlund, 1993, Sluka et al., 1994, Lawand et al., 1997, Min et al., 2001, Zhang et al., 2003, Zhang et al., 2009). Post-administration (3 h; 100 μl) of AP7 (0.2 mM), CNQX (0.1 mM) or ketamine (0.1 mM) into the knee synovial cavity reduces paw mechanical (von Frey, 30–100 mN) and thermal (thermal plantar) hyperalgesia during kaolin/carrageen (3%, 100 μl) induced
Pain during chronic inflammation
Injection of CFA initiates an acute inflammatory response that develops into AIA, a chronic arthritis-like inflammation. Glutamate release from and the EAARs on primary afferents influence the development and maintenance of nociceptive behaviors during chronic inflammation (Leem et al., 2001; Walker et al., 2001, Du et al., 2003, Du et al., 2006, Miller et al., 2010b). When administered during AIA, i.pl. injection of GLS inhibitors produces potent, long-lasting analgesia (Miller et al., 2010b).
Pain during chronic neuropathy
Several animal models of neuropathy are used and peripheral EAARs may have a role in the induction and/or maintenance of neuropathic pain (Aley & Levine, 2002). Systemic ketamine, memantin, NMDA antagonist, and 2S,4R-4-methylglutamate, KAR antagonist, are effective in reducing mechanical and thermal hyperalgesia and spontaneous pain in the sciatic nerve chronic constriction injury, freeze injury, and L5–6 spinal nerve ligation (Carlton and Hargett, 1995, Qian et al., 1996, Sutton et al., 1999,
Glutamate and human pain
This review has illustrated that inflammatory animal models cause increased levels of glutamate in peripheral tissues and that peripheral glutamate, interacting with numerous EAAR receptors, produces nociceptive behaviors. Other questions remain for human studies. Are glutamate levels elevated in peripheral tissues in patients with chronic painful conditions? Does peripheral glutamate cause pain in humans? Can inhibition of the peripheral glutamatergic system produce pain relief?
Summary
The current review has focused on the glutamatergic nature of peripheral terminals of primary afferents. These neurons are sensory transducers and transmitters, but they also interact with the peripheral environment by releasing and reacting to glutamate under various physiological and pathophysiological conditions. Intense noxious stimuli or inflammatory conditions cause primary afferent terminals to release glutamate into peripheral tissues. Many peripheral primary afferents have EAARs and
Acknowledgments
The authors thank the excellent technical support of Bharathi Srnivasan, Kristy Edwards, Brent Richards, Zijia Zhang, Jeff McCosh, Sheila Pete, and Sumit Aluwahlia.
Supported by NIH grants NS27213 and AR047410 (KEM).
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