Glutamate pharmacology and metabolism in peripheral primary afferents: Physiological and pathophysiological mechanisms

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Abstract

In addition to using glutamate as a neurotransmitter at central synapses, many primary sensory neurons release glutamate from peripheral terminals. Primary sensory neurons with cell bodies in dorsal root or trigeminal ganglia produce glutaminase, the synthetic enzyme for glutamate, and transport the enzyme in mitochondria to peripheral terminals. Vesicular glutamate transporters fill neurotransmitter vesicles with glutamate and they are shipped to peripheral terminals. Intense noxious stimuli or tissue damage causes glutamate to be released from peripheral afferent nerve terminals and augmented release occurs during acute and chronic inflammation. The site of action for glutamate can be at the autologous or nearby nerve terminals. Peripheral nerve terminals contain both ionotropic and metabotropic excitatory amino acid receptors (EAARs) and activation of these receptors can lower the activation threshold and increase the excitability of primary afferents. Antagonism of EAARs can reduce excitability of activated afferents and produce antinociception in many animal models of acute and chronic pain. Glutamate injected into human skin and muscle causes acute pain. Trauma in humans, such as arthritis, myalgia, and tendonitis, elevates glutamate levels in affected tissues. There is evidence that EAAR antagonism at peripheral sites can provide relief in some chronic pain sufferers.

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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