Inhibition by Spinal μ- and δ-Opioid Agonists of Afferent-Evoked Substance P Release

Abstract

Opioid -and ␦-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. ]-enkephalin (DPDPE) (1 M). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), deliveredat spinal cord segment L2 using intrathecal catheters. These doses of the and ␦ agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.

Inhibition of Inflammatory Pain by CRF at Peripheral, Spinal and Supraspinal Sites: Involvement of Areas Coexpressing CRF Receptors and Opioid Peptides

“…Consistent with a putative release of opioid peptides, ENK-ir interneurons are in close proximity of clusters of MOR-ir nociceptive neurons (Arvidsson et al, 1995) whose activation may contribute to presynaptic inhibition of sensory neuron neurotransmitter release (Kondo et al, 2005) and/or postsynaptic hyperpolarization of excitatory neurons (Trafton et al, 2000). Interestingly, i.t.…”

Removing TRPV1-expressing primary afferent neurons potentiates the spinal analgesic effect of δ-opioid agonists on mechano-nociception

“…It has been shown that the release of glutamate and substance P from primary afferent neurons is inhibited by δ-opioid agonists (Glaum et al, 1994;Kohno et al, 1999;Kondo et al, 2005). Thus, the presynaptic action of δ-opioid agonists on nociceptive afferent terminals has been considered an important mechanism underlying the spinal analgesic effect of δ-opioid agonists.…”

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…A prominent example is the inhibition of substance P and calcitonin gene-related peptide (CGRP) release (both are pronociceptive and proinflammatory neuropeptides) from central and peripheral terminals of primary afferent neurons ( Fig. 1) (Yaksh, 1988;Khasabova et al, 2004;Kondo et al, 2005). At the postsynaptic membrane, opioid receptors mediate hyperpolarization by opening G protein-coupled inwardly rectifying K ϩ (GIRK) channels, thereby preventing neuronal excitation and/or propagation of action potentials for review, see Lü scher and Slesinger, 2010).…”