μ-Opioid receptor inhibition of substance P release from primary afferents disappears in neuropathic pain but not inflammatory pain

Abstract

Opiate analgesia in the spinal cord is impaired during neuropathic pain. We hypothesized that this is caused by a decrease in μ-opioid receptor inhibition of neurotransmitter release from primary afferents. To investigate this possibility, we measured substance P release in the spinal dorsal horn as neurokinin 1 receptor (NK1R) internalization in rats with chronic constriction injury (CCI) of the sciatic nerve. Noxious stimulation of the paw with CCI produced inconsistent NK1R internalization, suggesting that transmission of nociceptive signals by the injured nerve was variably impaired after CCI. This idea was supported by the fact that CCI produced only small changes in the ability of exogenous substance P to induce NK1R internalization or in the release of substance P evoked centrally from site of nerve injury. In subsequent experiments, NK1R internalization was induced in spinal cord slices by stimulating the dorsal root ipsilateral to CCI. We observed a complete loss of the inhibition of substance P release by the μ-opioid receptor agonist [D-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) in CCI rats but not in sham-operated rats. In contrast, DAMGO still inhibited substance P release after inflammation of the hind paw with complete Freund’s adjuvant and in naïve rats. This loss of inhibition was not due to μ-opioid receptor downregulation in primary afferents, because their colocalization with substance P was unchanged, both in dorsal root ganglion neurons and primary afferent fibers in the dorsal horn. In conclusion, nerve injury eliminates the inhibition of substance P release by μ-opioid receptors, probably by hindering their signaling mechanisms.

Expression of mu opioid receptor in dorsal diencephalic conduction system: New insights for the medial habenula

“…Previous literature has documented functional interactions between opioid and substance P systems. At the level of the spinal cord, dorsal root ganglia and primary afferents, opiates acting at MORs inhibit Substance P release and alleviate pain transmission (Beaudry et al, 2011, Suzuki et al, 2012, Chen et al, 2014, Mizoguchi et al, 2014). Several studies also correlate substance P release and concentration with the severity of morphine withdrawal symptoms (Johnston and Chahl, 1991, Maldonado et al, 1993, Buccafusco and Shuster, 1997, Zhou et al, 1998, Trang et al, 2002, Michaud and Couture, 2003, Gu et al, 2005).…”

Transmission pathways and mediators as the basis for clinical pharmacology of pain

“…Since one of the primary effects of opioids is significant inhibition of Substance P release, research suggesting a limited role of neurokinins in pain transmission seemed somewhat perplexing [173]. More recent studies by Chen et al [173] showed that only inflammatory (and not neuropathic) pain responded to Substance P inhibition in rat test subjects.…”

“…More recent studies by Chen et al [173] showed that only inflammatory (and not neuropathic) pain responded to Substance P inhibition in rat test subjects. This further supports the established role of Substance P as an inducer of inflammation [176].…”

Clinical Updates on Substance-P Antagonist in Pain Management

“…Substance P (SP) is considered as the prototypic neuropeptide of the more than 50 known neuroactive molecules, and is also the member of a new neurotransmitter system that belongs to the family of three related peptides known as neurokinins and a member of the seven-transmembrane G-protein coupled family of receptors and is primarily associated with sensory neurons in the periphery and specific areas of the CNS [1,2]. The other two members are simply called neurokinin A and neurokinin B. Modulation of SP activity offered a radical new approach to the management of depression, anxiety, stress and is involved in several physiologic activities, including the vomiting reflex, defensive behavior, change in cardio-vascular tone, stimulation of salivary secretion, smooth muscle contraction and vasodilatation [3,4].…”