Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception

doi:10.1016/0028-3908(94)90052-3

Neuropharmacology

Volume 33, Issue 11, November 1994, Pages 1479-1485

https://doi.org/10.1016/0028-3908(94)90052-3 Get rights and content

Abstract

In the present investigation we have tested the hypothesis that spinal glutamate release by inflammatory stimuli causes hyperalgesia through sensitization of the primary sensory neurons associated with nociception. In these experiments, the rat paw hyperalgesia pressure test in which inflammatory hyperalgesia is blocked by the intraplantar administration of morphine (MPH) or SNAP, a NO donor was used. Glutamate and glutamatergic ionotropic agonists such as NMDA or AMPA injected intrathecally (i.t.) caused a dose-dependent hyperalgesia. Quisqualate or ACPD, both of which are glutamate metabotropic receptor agonists, had no hyperalgesic effect. The hyperalgesic response to glutamate and NMDA injected i.t. was antagonized by the intraplantar (i.pl.) injection of either MPH or SNAP. This observation indicates that the hyperalgesia induced by glutamate acting through an NMDA pre-synaptic receptor causes sensitization of the primary sensory neurons. Confirming that the analgesia by i.pl. injection of SNAP or MPH was due to an action in primary peripheral sensory neurons, it was shown that pretreatment of the paws with methylene blue (MB, an inhibitor of guanylate cyclase) or with MB and l-NMMA (an inhibitor of NO synthase) abolished their respective analgesic effect. AMPA i.t. induced hyperalgesia was not inhibited by either i.pl. administration of MPH or SNAP, indicating that its hyperalgesic capacity results from an action at a site other than the primary sensory neuron. Administration of the NMDA antagonists AP5 and MK801, but not the AMPA antagonist CNQX, inhibited the hyperalgesia induced by intraplantar injections of PGE₂ or carrageenin. Overall, our results indicate that hyperalgesia evoked by an inflammatory stimulus in this model causes a continuous release of spinal glutamate which, via an NMDA-type receptor, promotes a retrograde sensitization of the primary sensory neurons.

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Whereas it is commonly held that peripheral changes lead to central sensitization, paradoxically, changes in the chemical milieu in the spinal cord can lead to sensitization of primary sensory neurons in a retrograde fashion. For example, intrathecal injection of glutamate, NMDA, or prostaglandin E2 (PGE2) can cause mechanical hyperalgesia which can be attenuated by intraplantar injection of either morphine or the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) (Ferreira and Lorenzetti, 1994, 1996). The authors hypothesize that once central terminals of primary afferents are sensitized, the change in membrane properties are rapidly extended by some unknown mechanism, resulting in “retrograde sensitization” of peripheral terminals of primary afferent.
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Interestingly, it has been demonstrated that intraplantar (i.pl.) injection of morphine abolishes ipsilateral hyperalgesic response to i.t administration of NMDA, but not AMPA, without affecting response of the contralateral paw (Ferreira and Lorenzetti, 1994). Antisense oligodeoxynucleotide-mediated reduction of expression of the NaV1.8 voltage-gated sodium channel, which is preferentially distributed in small diameter DRG fibers (Gold, 1999), prevents the nociception induced by i.t. NMDA (Parada et al., 2003).
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Nociceptors can be sensitized following strong noxious stimuli or by exposure to inflammatory mediators or low pH (Bessou and Perl, 1969; Fitzgerald and Lynn, 1977; Meyer and Campbell, 1981; LaMotte et al., 1982, 1983; Kocher et al., 1987; Reeh et al., 1987; Häbler et al., 1990; Kirchhoff et al., 1990; Handwerker et al., 1991; Schmelz et al., 1996; Willis and Coggeshall, 2004). The following substances can induce sensitization of nociceptors by interactions with surface membrane receptors: bradykinin (Rueff and Dray, 1993a; Schuligoi et al., 1994; Liang et al., 2001; Shin et al., 2002); catecholamines (Gold et al., 1994; Khasar et al., 1999); cytokines (Sorkin et al., 1997); excitatory amino acids (Ferreira and Lorenzetti, 1994; Du et al., 2001); inflammatory soup (a mixture of bradykinin, histamine, serotonin, and prostaglandin E1) (Kessler et al., 1992; Davis, et al., 1993; Kress et al., 1997); neurokinins and other peptides (Nakamura‐Craig and Gill, 1991; Kessler et al., 1992); prostaglandins and other arachidonic acid products (Martin et al., 1987; Cohen and Perl, 1990; Martin, 1990; White et al., 1990; Schepelmann et al., 1992; Rueff and Dray, 1993a,b; Chen et al., 1999); protons (Steen et al., 1992, 1996); and serotonin (Rueff and Dray, 1993b). Growth factors, such as NGF, also contribute to the sensitization of nociceptors during inflammation (Koltzenburg et al., 1999).
This chapter provides an overview of the nociceptive membrane. Nociceptors are primary afferent neurons that signal tissue damage or the threat of tissue damage. Nociceptors are found in the skin and subcutaneous tissue, muscle, joints, and viscera. They also supply the meninges, although they do not intrude into the central nervous system (CNS). Nociceptors have unencapsulated terminals in the tissue that they innervate. The axons of cutaneous nociceptive afferents are either ﬁnely myelinated (Aδ) or unmyelinated (C) ﬁbers. Nociceptors that supply muscle or joints are also finely myelinated and unmyelinated afferents, but a different nomenclature is used; these are referred to as group III and group IV fibers. Although the terminals of nociceptors are often described as “free nerve endings,” much of the terminal membrane of nociceptors is covered by Schwann cells. However, there are membrane areas that are exposed to the extracellular space. The ability of an individual nociceptor to respond to different types of noxious stimuli would depend on the presence or absence of particular transduction molecules in its surface membrane.

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Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception

Abstract

Pain

Neurosci. Lett.

Brain Res.

Eur. J. Pharmac.

Prostaglandins

Prostaglandins

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Brain Res.

Eur. J. Pharmac.

Neurosci. Lett.

Pain

TINS

Pain

Pain

Neurosci. Lett.

Pain

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Eur. J. harmac.

Brain Res.