Neuropathic Pain
Mark V. Boswell, B. Eliot Cole in Weiner's Pain Management, 2005
Although, under certain circumstances, dynorphin appears to have analgesic properties, it is becoming increasingly clear that dynorphin also has nonopioid, antianalgesic properties. Antiserum to dynorphin blocks thermal hyperalgesia after nerve injury in rats. Moreover, antiserum to dynorphin or MK801, an NMDA antagonist, restores normal spinal morphine analgesia following spinal nerve ligation. Furthermore, both agents restore morphine synergy between the brain and spinal cord (Ossipov et al., 2000), which is required for the full clinical analgesic effects of morphine. Therefore, current evidence suggests that the pain-promoting effect of dynorphin is mediated by the NMDA receptor. Although the full clinical ramifications of dynorphin are far from understood, it is clear that sustained nociceptive drive from the periphery maintains elevated levels of spinal dynorphin, which, in turn, may have toxic effects on the spinal cord. Thus, reducing sustained peripheral nociceptive input into the spinal (i.e., pain relief) may be an important way to reduce the incidence of neuropathic pain (Caudle & Mannes, 2000).
Physiology of the Pain System
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
The limbic system is a set of brain structures on either side of the thalamus that directs emotion, behavior, motivation, long-term memory, and olfaction. The mesolimbic pathway is part of the reward circuit. Dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain project to the forebrain nucleus accumbens (NAc). Burst firing of dopaminergic neurons into the NAc serves as a reward signal and is inhibited by tonic GABA input.15 Opioids inhibit GABAergic tone on these neurons, while pain relief directly engages dopamine circuitry.15 The mesolimbic pathway has been implicated in depression, anxiety, pain sensation, anticipation of analgesia or placebo-induced analgesia, and chronic pain.16 Different types of pain can impact different aspects of the VTA and result in either activation or inhibition. In this way, dopamine release is variable based on various pain signals.16 These dopaminergic pathways are variably altered with stress as well as opioids. Dynorphin and the kappa opioid receptor can play a role in impairing dopamine release in the Na.16
Postulated Physiological and Pathophysiological Roles on Motility
Edwin E. Daniel in Neuropeptide Function in the Gastrointestinal Tract, 2019
Intra-arterial or i.v. application of morphine or other opioids excites the canine8–10,384,492,509,510,545,546 and human small intestine.509,511 It has been demonstrated that cholinergic384,510 as well as serotonergic546 mechanisms are involved in this excitatory response. Met-enkephalin given intra-arterially caused excitation of the canine small intestine in vivo, but excitation did not occur in vitro.8 This excitation to intra-arterially injected opioids was partially abolished by atropine, suggesting that opioids might cause the release of acetylcholine. When opioids were given intra-arterially during excitation using field stimulation, the same opioids were inhibitory; see Figure 12. Dynorphin, which has little or no excitatory effect, was the most potent inhibitor.8,9 Interestingly, the excitatory effect of motilin involved an NANC component which was blocked by naloxone, suggesting the release of endogenous opioids by motilin.9
Neuropharmacological basis for multimodal analgesia in chronic pain
Published in Postgraduate Medicine, 2022
Ryan Patel, Anthony H Dickenson
The pain-relieving properties of naturally occurring opioids have been utilized for centuries, and today opioids remain the mainstay of treating acute and chronic pain. Morphine has become the gold standard analgesic to which all others are compared. The classical opioid receptors μ, δ and κ are G-protein coupled, and later a fourth opioid-like receptor (ORL1) was described and renamed the nociceptin receptor. Soon after, a series of endogenous peptide ligands were described. Most of these bind to multiple receptors through endomorphin-1/2 and β-endorphin have highest affinity for μ-opioid receptors, met- and leu-enkephalin have highest affinity δ-opioid receptors, dynorphin A/B have highest affinity κ-opioid receptors, and nociceptin/orphanin FQ has highest affinity for the nociceptin receptor [69]. Upon receptor activation neuronal excitability or action potential propagation is inhibited by several mechanisms including opening of G protein–coupled inwardly rectifying potassium channels [70], inhibition of sodium [71] and calcium channels [72], and inhibition of Ih currents [73].
Prodynorphin (PDYN) gene polymorphisms in Turkish patients with methamphetamine use disorder, changes in PDYN serum levels in withdrawal and the relationship between PDYN, temperament and depression
Published in Journal of Ethnicity in Substance Abuse, 2022
Güliz Şenormancı, Çetin Turan, Sevim Karakaş Çelik, Aycan Çelik, Tuba Gökdoğan Edgünlü, Dilek Akbaş, Ayşe Semra Demir Akca, Ömer Şenormancı
In a study conducted in the postmortem period, it was shown that dynorphin mRNA levels and dynorphin protein increased in chronic cocaine users (Frankel et al., 2008). Preclinical studies have evidenced that dynorphin peptides attenuate the extracellular dopamine increase in nucleus accumbens (Zhang et al., 2005). It has been suggested that the dynorphin K opioid system is a regulatory system that reverses substance-induced dopaminergic stimulation and may play a role in the development of dependence (Koob & Kreek, 2007). Chronic methamphetamine exposure stimulates dopamine receptors in nucleus accumbens, leading to an increase in PDYN, which results in the emergence of withdrawal symptoms by decreasing dopamine through k opioid receptors (Nomura et al., 2006).
Can pharmacotherapy improve treatment outcomes in people with co-occurring major depressive and cocaine use disorders?
Published in Expert Opinion on Pharmacotherapy, 2021
Gustavo A. Angarita, Hasti Hadizadeh, Ignacio Cerdena, Marc N. Potenza
Another possible target is the kappa-opioid receptor (KOR)/dynorphin system. Chronic cocaine exposure is associated with upregulation of KORs and its endogenous ligand dynorphin [86]. Increased levels of dynorphin in the NAc inhibit dopamine release [87] and may influence negative emotional states, termed hyperkatifeia, following withdrawal (i.e. dysphoria/anhedonia, aversion and depression/anxiety) [88]. A negative reinforcement cycle, in which individuals find themselves experiencing undesirable emotional states and see drug use as a short-term option to decrease them, has been termed the ‘Dark Side of Addiction’ [89], and the dynorphin/KOR system contributes to this antireward/stress system[88] .
Related Knowledge Centers
- Dynorphin
- Opioid Peptide
- Κ-Opioid Receptor
- Protein Primary Structure
- Opioid Receptor