Effects of Intrathecal SNC80, a Delta Receptor Ligand, on Nociceptive Threshold and Dorsal Horn Substance P Release

Abstract

Delta-opioid receptors (DOR) are present in the superficial dorsal horn and are believed to regulate the release of small afferent transmitters as evidenced by the effects of spinally delivered delta-opioid preferring peptides. Here we examined the effects, a selective nonpeptidic DOR agonist, in three preclinical pain models, acute thermal escape, intraplantar carrageenan-tactile allodynia, and intraplantar formalin flinches, and on the evoked release of substance P (SP) from small primary afferents. Rats with chronic intrathecal catheters received intrathecal vehicle or SNC80 (100 or 200 mg). Intrathecal SNC80 did not change acute thermal latencies or carrageenan-induced thermal hyperalgesia.However, SNC80 attenuated carrageenan-induced tactile allodynia and significantly reduced both phase 1 and phase 2 formalininduced paw flinches, as assessed by an automatic flinch counting device. These effects were abolished by naltrindole (3 mg/kg i.p.), a selective DOR antagonist, but not CTOP (10 mg i.t.), a selective MOR antagonist. Furthermore, intrathecal SNC80 (200 mg) blocked formalin-induced substance P release otherwise evoked in the ispilateral superficial dorsal horn as measured by NK1 receptor internalization. In conclusion, intrathecal SNC80 alleviated pain hypersensitivity after peripheral inflammation in a fashion paralleling its ability to block peptide transmitter release from small peptidergic afferents, which by its pharmacology appears to represent an effect mediated by a spinal DOR.

Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal Horn

“…Note also that Wang et al omitted to consider the possibility that convergent inputs from distinct DOR+ and MOR+ fibers can modulate neurotransmitter release onto a given spinal neuron, without requiring coexpression of the two receptors in the same primary afferent neurons. Similarly, data on the inhibition of spinal SP release by intrathecal DOR agonists (for example (Beaudry et al, 2011; Kouchek et al, 2013)) should be interpreted carefully, because both SP and DOR are expressed, and possibly coexpressed, by numerous spinal neurons, thus preventing definitive conclusions to be drawn regarding DOR and SP coexpression in DRG neurons. By contrast, CGRP is restricted to primary afferent terminals in the dorsal horn, and our data showing DOR and CGRP coexpression in large-diameter NF200+ DRG neurons, and DOR-mediated inhibition of VGCCs in these cells, are consistent with the idea that DOR agonists can reduce CGRP release (Overland et al, 2009) and further suggest this effect results mostly from an action on myelinated nociceptors.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Furthermore, only animals with an inflammatory response displayed analgesic responses to SNC80 injection ; since the drug was administered systemically, it is difficult to ascertain the specific contribution of Cav2 channel modulation to this analgesic response. On the other hand, studies using intrathecal administration of SNC80 or deltorphin II indicated reduced substance P release in a formalin pain model but not in acute thermal escape (Beaudry et al, 2011;Kouchek et al, 2013), supporting the overall idea that inflammation potentiates DOPr inhibitory actions on sensory neurons.…”

“…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).…”

Recent advances on the δ opioid receptor: from trafficking to function

“…Functional evidence for the expression of DOPr in these neurons also exists. In small peptidergic neurons, DOPr was indeed shown to be involved in the inhibition of glutamate, substance P and CGRP release (Ueda et al ., ; Zachariou and Goldstein, ; Beaudry et al ., ; Overland et al ., ; Kouchek et al ., ; Normandin et al ., ). DOPr was also found to synergize with α 2A ‐adrenergic receptors in peptidergic primary afferents via a PKC‐dependent mechanism (Overland et al ., ; Riedl et al ., ; Schuster et al ., ).…”