Capsaicin-Induced Glutamate Release Is Implicated in Nociceptive Processing Through Activation of Ionotropic Glutamate Receptors and Group I Metabotropic Glutamate Receptor in Primary Afferent Fibers

Abstract

Abstract. Glutamate (Glu) is the major excitatory neurotransmitter in the central nervous system. The role of peripheral Glu and Glu receptors (GluRs) in nociceptive transmission is, however, still unclear. In the present study, we examined Glu levels released in the subcutaneous perfusate of the rat hind instep using a microdialysis catheter and the thermal withdrawal latency using the Plantar Test following injection of drugs associated with GluRs with / without capsaicin into the hindpaw. The injection of capsaicin into the rat hind instep caused an increase of Glu level in the s.c. perfusate. Capsaicin also significantly decreased withdrawal latency to irradiation. These effects of capsaicin were inhibited by pretreatment with capsazepine, a transient receptor potential vanilloid receptor 1 (TRPV1) competitive antagonist. Capsaicin-induced Glu release was also suppressed by combination with each antagonist of ionotropic GluRs (iGluRs: NMDA / AMPA receptors) and group I metabotropic GluR (mGluR), but not group II and group III mGluRs. Furthermore, these GluRs antagonists showed remarkable inhibition against capsaicin-induced thermal hyperalgesia. These results suggest that Glu is released from the peripheral endings of small-diameter afferent fibers by noxious stimulation and then activates peripheral iGluRs and group I mGluR in development and/ or maintenance of nociception. Furthermore, the activation of peripheral NMDA / AMPA receptors and group I mGluR may be important in mechanisms whereby capsaicin evokes nociceptive responses.

Group II mGluRs suppress hyperexcitability in mouse and human nociceptors

“…An analogous result was observed when nociceptor fiber discharge during a brief heat stimulus was not attenuated by APDC, but the discharge generated by the longer-lasting algogen capsaicin was reduced [6]. The release of glutamate into the skin by keratinocytes [19] or reflex activation of the peripheral terminals of primary afferent fibers [25; 30] under injury or inflammatory conditions could produce endogenous activation of group II mGluRs leading to negative feedback and inhibition of the ongoing response. This schema is consistent with the presynaptic inhibitory effect of group II mGluRs reported in other parts of the nervous system [42], with the receptive peripheral ending from these pseudo-unipolar axons functioning analogously to a presynaptic terminal.…”

Investigating the expression of metabotropic glutamate receptors in trigeminal ganglion neurons and satellite glial cells: implications for craniofacial pain

“…For instance, it has been reported that knocking down mGluR1 in rat lumbar spinal cord could reduce hyperalgesia dramatically (31). Moreover, mGluR1 antagonists MPEP and 7-(hydroxyimino) cyclopropa[ b ]chromen-1 a-carboxylate ethyl ester (CPCCOEt) proved successful in blocking capsaicin-induced glutamate release, indicating that mGluR1 activation may influence nociception through modulation of glutamate release (32). Recent evidences demonstrated that application of a group I mGluR selective agonist (DHPG) on DRG neurons could cause a significant increase in inward calcium currents (9), which could enhance the release of glutamate from neurons.…”

Peripheral Glutamate Receptors Are Required for Hyperalgesia Induced by Capsaicin

“…Intraplantar injection of L-glutamate or iGluR agonists into the hindpaw evokes thermal and mechanical hyperalgesia and allodynia, which can be blocked by appropriate antagonists [7, 10–12]. …”

“…A broad range of stimuli such as noxious heat, protons, lipid-derived endovanilloids, and inflammatory mediators either directly activate or modulate TRPV1 [13, 14], and stimulation of TRPV1 elicits the release of glutamate [12, 15, 16]. At the peripheral terminals of primary afferents, TRPV1-mediated Ca 2+ influx triggers the release of neuropeptides and neurotransmitters, which is responsible for nociceptive processing [14].…”

“…We also observed that GluRs, in particular, iGluRs and group I mGluR existing in peripheral endings of capsaicin-sensitive afferent fibers, play an important role in the development and maintenance of hyperalgesia following excitation of TRPV1 by determining the changes of glutamate levels in the extracellular space of rat hindpaw and pain behavior in the thermal withdrawal latency [12]. …”