Activation of Spinal μ- and δ-Opioid Receptors Potently Inhibits Substance P Release Induced by Peripheral Noxious Stimuli

Abstract

Over the past few years, ␦-opioid receptors (DOPRs) and -opioid receptors (MOPRs) have been shown to interact with each other. We have previously seen that expression of MOPR is essential for morphine and inflammation to potentiate the analgesic properties of selective DOPR agonists. In vivo, it is not clear whether MOPRs and DOPRs are expressed in the same neurons. Indeed, it was recently proposed that these receptors are segregated in different populations of nociceptors, with MOPRs and DOPRs expressed by peptidergic and nonpeptidergic fibers, respectively. In the present study, the role and the effects of DOPR-and MOPR-selective agonists in two different pain models were compared. Using preprotachykinin A knock-out mice, we first confirmed that substance P partly mediates intraplantar formalin-and capsaicin-induced pain behaviors. These mice had a significant reduction in pain behavior compared with wild-type mice. We then measured the effects of intrathecal deltorphin II (DOPR agonist) and DAMGO (MOPR agonist) on pain-like behavior, neuronal activation, and substance P release following formalin and capsaicin injection. We found that both agonists were able to decrease formalin-and capsaicin-induced pain, an effect that was correlated with a reduction in the number of c-fos-positive neurons in the superficial laminae of the lumbar spinal cord. Finally, visualization of NK 1 (neurokinin 1) receptor internalization revealed that DOPR and MOPR activation strongly reduced formalin-and capsaicin-induced substance P release via direct action on primary afferent fibers. Together, our results indicate that functional MOPRs and DOPRs are both expressed by peptidergic nociceptors.

Expression of substance P, calcitonin gene-related peptide, β-endorphin and methionine-enkephalin in human dental pulp tissue after orthodontic intrusion: A pilot study

“…Accordingly, each substance may not exert individual effects but rather may produce cross-control mechanisms, especially as the source of both neuropeptides also expresses m opioid and d opioid receptors for Met-Enk and b-End. 16,37 This hypothetical correlation and its relevance must be evaluated in further research. Also, further studies with more patients are needed to confirm these findings.…”

“…12,13 Met-Enk and bEnd are capable of stimulating m and d opioid receptors and d opioid receptors, respectively, causing direct analgesia 14,15 by attenuation of neuronal excitability and neuropeptidergic release. 16 Until now, only a few reports have explored the relationship between the development of neurogenic inflammation caused by neuropeptides and the local pain modulation mechanisms mediated by the presence of endogenous opioids in the dental pulp environment. The aim of this study was to determine the levels of two sensory neuropeptides (SP and CGRP) and two endogenous opioids (Met-Enk and bEnd) in dental pulp tissue samples subjected to controlled orthodontic intrusive forces.…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…The m-opioid receptor agonist morphine is a potent clinically used analgesic that interacts with m-opioid receptors (Mizoguchi et al, 2012), which then inhibits Ca V 2.2 channels in dorsal horn synapses (Heinke et al, 2011), along with concomitant activation of G protein-coupled inward rectifier potassium channels (Marker et al, 2005). The receptorinduced inhibition of Ca V 2.2 channels is thought to reduce presynaptic calcium levels, which in turn reduces synaptic transmission between these afferent nerve terminals (Kondo et al, 2005;Beaudry et al, 2011). Morphine also acts at m-opioid receptors that are expressed in the CNS (Diaz et al, 1995;Goodchild et al, 2004), where a clear correlation between physiologic effects and modulation of Ca V 2.2 channels is more difficult to establish.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Finally, an insufficient population of DOPrs is present in substance P-containing neurons to produce a physiologic effect (Bardoni et al, 2014). Nevertheless, DOPr immunoreactivity was identified in substance P neurons within the myenteric plexus of the small intestine of DOPr-eGFP knock-in mice (Poole et al, 2011), demonstrating that DOPrs can be coexpressed with substance P. Moreover, DOPr activation also inhibits substance P release from primary afferents (Beaudry et al, 2011;Kouchek et al, 2013;Normandin et al, 2013). The dispute over whether DOPrs are present in substance P-containing neurons remains unresolved, because in situ hybridization and single-cell polymerase chain reaction studies report different results Wang et al, 2010).…”