State-dependent opioid control of pain

“We now know a great deal about the molecular mechanisms of transduction and the relationship of the firing of these neurons to stimulus intensity and to the psychophysics of perceived pain intensit”

“This system is the driving force behind the natural 73 suppression or enhancement of pain in different behavioral states (Fields 2004).”

“These alterations in a brain structure with a well documented role in the antinociception of pain [30,31] and in fear and defence behaviour [32], are therefore likely to contribute to the blunted perception of dyspnea at least in subgroups of patients with asthma.”

“…and colleagues used extracellular recording methods to characterize the responses of RVM neurons to noxious stimuli in vivo and proposed that RVM neurons can be assigned to one of three functional classes, termed ON, OFF, and NEUTRAL cells (Fields 2004; Fields et al. 1983; Vanegas et al. 1984).”

“Nonsteroidal anti-inflammatory drugs (NSAIDS), or nonselective cyclo-oxygenase-1/2 (COX1/2) inhibitors, as well as selective COX2 inhibitors, are also commonly used to manage inflammation and pain in NP, particularly in sub-acute and acute-on-chronic phases [34,35].”

“The classical opioid system is best known for its effects on nociception (Fields, 2004); however, it is also important for modulating the immune system and releasing Ca2+ from intracellular stores.”

“These different determinants of drug self-administration may blur in that they reflect similar central mechanisms (Fields, 2004).”

“Remarkably, it has also been reported that the connectivity between ventral striatum and PFC predicts the prognosis of chronic pain [59], and (4) all cortical inputs converge to the PAG-RVM-spinal cord, which facilitates or inhibits nociception [46, 54].”

“The importance of endogenous ENK signaling in RVM descending inhibition is in agreement with previous work (al-Rodhan et al., 1990; Fields, 2004).”

“Indeed, the interaction of opioid and serotonin systems in producing analgesia has been widely demonstrated over several years (Watkins and Mayer 1986; Lipp 1991 )t hrough the regulation of centralμ and κ receptors ( Fields 2004 ).”

“Opioid receptors can inhibit multiple levels of the ascending pain pathways for pain signal transmission in supraspinal regions related to nociceptive message integration and participate in facilitatory and inhibitory descending pathways [13,38,39].”

“These neurons give rise to the main ascending trigeminothalamic pathway that carries sensory information to third order neurons in the thalamus, before processing the information to higher cortical areas (115).”

“Recent studies have identified specific neural circuits in the PAG and the RVM promoting either pain inhibition or pain facilitation ( 13 – 17 ).”

“Stress-induced analgesia was an important stimulus to research in the latter half of the twentieth century: excitement was in part because delineation of the circuitry mediating stress-induced analgesia demonstrated the existence of an intrinsic capacity to modulate pain, and also because this same circuitry was disco…”

“Traditionally, the various forms of endogenous pain modulation have been viewed as a set of regulatory mechanisms that enable the organism to inhibit or amplify nociceptive signals pursuant to internal or environmental biological needs (Basbaum et al., 2009; Fields, 2004; Millan, 2002).”

“Indeed, evidence shows that opioid-mediated pain circuits are activated during appetitive circumstances (Fields, 2004).”

“One of the best characterised of these peptides, β-endorphin [6], has been shown to play roles in endogenous analgesia and stress responses [7] as well as being linked to reward processing [8], feeding [9] and cardiorespiratory regulation [10].”

“the release of endogenous opioid peptides and subsequent agonism of OpRs in the central nervous system.(19) However,”

“-opioid receptor; raphe magnus; -aminobutyric acid; glutamate decarboxylase THE ROSTRAL VENTROMEDIAL MEDULLA (RVM) forms part of a descending pathway that is an important site for the supraspinal antinociceptive actions of opioids (Fields 2004).”

“Grill and Coghill (2002) also suggest central mechanisms play a role in offset analgesia and imply that the effect is due to activation of central inhibitory mechanisms such as descending influence from the periaqueductal grey (PAG) via the rostral ventromedial medulla (RVM) (Budai et al., 1998; Fields, 2004; Tracey a…”

“The opioid system plays a relevant role in driving placebo effects as demonstrated by pharmacological and imaging studies.(2,21,23,34,48,49) Peciña and colleagues first examined the”

“The most investigated form of the physiological activation of opioid-linked pain-modulating circuits originates under the general framework of stress-induced analgesia (7, 46).”

“Studies suggest that the endogenous opioid system is essential for both placebo and nocebo effects (Amanzio and Benedetti, 1999; Benedetti et al., 1999; Fields, 2004; Petrovic et al., 2002).”

“Then, we investigated whether pharmacologically blocking opioidergic activity (with an opioid receptor antagonist), which is one of the main neurochemical mechanisms of placebo analgesia and also plays a central role in pain and its regulation (Fields, 2004 for review), would revert these effects.”

“The rostral ventral medulla (RVM) contains another family of neuromodulatory neurons in the brainstem that send descending serotonergic projections to the spinal cord.(11,48,81) However, serotonin has both excitatory and inhibitory effects in the dorsal horn, and electrical stimulation of the RVM produced both pronoci…”

“The m-opioid receptor (MOR) system, central to reward and pain regulation across species (Fields, 2004), is also important for social reward such as bonding behaviors in rodents and primates (Herman and Panksepp, 1978; Panksepp, 1980; Moles et al., 2004; Machin and Dunbar, 2011; Løseth et al.,…”

“A possibly similar model of opioidinduced disinhibition is the opioid effects on the supraspinal analgesic pathway (Fields, 2004).”

“It plays an important role in the development and maintenance of the behavioral state of sensitized pain and opioid analgesia under chronic pain conditions (45, 46).”

“As well known, the DPMS played an essential role in pain modulation and the physiopathology of chronic pain (Fields, 2004; Borsook and Burstein, 2012; Ossipov et al., 2014).”

“The late positive potential has negative maximum in the parieto-occipital and positive maximum in frontal and central electrodes (Foti et al., 2009), which map was similar to the topographic map shown in Figure 4A in our study.”

“…at the level of first-order primary afferent neurons and extend to higher-order thalamic and cortical levels where pain messages are integrated, as well as descending inhibitory pain pathways, which recruit mainly brain stem and spinal cord networks (Fields, 2004; Dickenson and Kieffer, 2006).”

“Moreover, it has been suggested that these actions may lead to analgesia via presynaptic desinhibitory mechanisms (Porreca et al., 2002; Vaughan et al., 2003; Fields, 2004).”

“Upon activation, these Class A GPCRs induce a strong hyperpolarisation of MOR-expressing neurons and inhibit the transmission of nociceptive signals (Fields, 2004).”

“Since some have argued that analgesia may be a special case of reward processing—pain relief may be thought to be rewarding in and of itself (Fields 2004; Irizarry and Licinio 2005)—researchers have been interested in examining the contributions of dopamine systems to placebo analgesia.”

“When the decision to avoid potential injury is outweighed by the motivation to pursue a conflicting goal (eg, a significant reward), top–down processes in the brain inhibit nociception through release of opioid peptides; conversely, if the decision is to ignore the conflicting goal and instead to respond to the noxiou…”

“In rats, it was found to decrease the stress-induced behavioral effects and to decrease the pentobarbital sleeping time [20,21].”

“The antinociceptive function of the PAG is conveyed to the spinal cord largely by way of the RVM (Fields, 2004), and in models of acute pain the action of metamizol upon PAG triggers”

“However, the δ- and κ-opioid receptors (DORs and KORs) are also important in pain modulation (Fields, 2004; Corder et al., 2018).”

“…incoming noxious inputs via projections to the rostral ventromedial medulla, a region which contains “ON” and “OFF” cells that can increase and decrease the excitability of neurons in the dorsal horn, respectively (Fields et al., 1983; Fields, 2004; Hellman and Mason, 2012; Salas et al., 2016).”

“In addition, network analyses have revealed that expectation effects are mirrored by changes in coupling in the descending pain modulatory system (Porreca et al., 2002; Fields, 2004; Tracey and Dunckley, 2004), in particular between the mPFC and the periaqueductal gray (PAG) (Bingel et al.”

“Several reviews have discussed these pain pathways in detail (Millian, 2002; Fields, 2004; Vogt, 2005).”

“Thus, top-down endogenous opioid-enriched circuits modulate pain experience and can be triggered by conditioned or learned associations between an intervention and its purported analgesic properties (Fields, 2004).”

“…NAc for two reasons; first, both vlPAG (Fields, 2004; Reynolds, 1969) and NAc core (Gear et al., 1999; Gear and Levine, 2011; Tobaldini et al., 2014) have key roles in pain modulation. vlPAG for example, controls the descending pain modulation system in an opioid dependent manner (Fields, 2004).”

“Functional connectivity analysis showed significant correlation between pgACC and PAG, basal ganglia, and lower pons activities, in other words the descending pain inhibitory pathway (107,108)”

“surveys have reported that to reduce AEs associated with opioid treatment, specifically gastrointestinal (GI)-related AEs, patients often discontinue their opioid treatment [20,23,24].”

“Appetitive motivation may activate descending pain inhibitory pathways.(42) Evidence suggests that cognitive distraction tasks during noxious stimulation increase activity in the periacqueductal gray region of the midbrain, an area associated with inhibition of sensory processing of noxious signals.”

“NRM cells that lack MOR, or primary cells, are likely responsible for analgesic opioid-activated descending pain inhibition (Pan et al., 1997, 2000; Fields, 2004).”

“Altered functional connectivity in the descending pain-modulatory system predicts remifentanil offset-related increase in pain sensitivity As -opioid receptor agonists unfold part of their analgesic properties by acting on the pain-modulatory system (Barton et al., 1980; Fields, 2004; Haghparast et al., 2008), changin…”

“The demonstration of increased connectivity between DLPFC and PAG in our study is in line with the idea that prefrontal mechanisms trigger pain control systems descending from the brainstem (Basbaum and Fields, 1984; Fields, 2004).”

“A previous study showed that expectancies reduce stress and pain [17], which may be mediated by activation of the endogenous opiate system that is a part of the descending pain-modulating networks, as is the casewith placebo analgesia engendered by cognitive and motivational factors [18].”

“That is, when performing spinal cord stimulation, the amount of improvement depends on the activation of the pgACC (Moens et al., 2012), which is part of the descending pain inhibitory pathway (Fields, 2004; Kong et al., 2010), the somatosensory analog of the noise canceling system.”

“Pain is processed by at least three pathways, two ascending pain generating pathways (4,5) and at least one descending pain inhibitory pathway (6).”

“rACC and PAG are part of the descending pain control system that modulates spinal transmission of nociceptive information predominantly via opioidergic transmission [39].”

“21”

“It may be that opiates and gabapentin exert their antitussive action by potentiating these pathways [20].”

“…the detailed signaling cascades responsible for DOR inhibition of GABA neurotransmission and for DOR-mediated behavioral antinociception in brainstem neurons of the nucleus raphe magnus (NRM), an important supraspinal structure for opioid modulation of pain (Pan et al., 1997; Fields, 2004).”

“14,15 The ventrolateral periaqueductal gray (vlPAG) is a key regulator of this pathway, 16 and electrical, 17–24 pharmacological, 17,19,25–33 and chemogenetic 14,34–36 manipulation of this region produces profound analgesia. vlPAG is also a key site of endorphin-mediated analgesia, 22 and direct…”

“Despite their risks, opioids, such as morphine, are the main treatment option for neuropathic pain, but have limited effectiveness in patients with this debilitating disorder (Fields, 2004; Cooper et al., 2017; Els et al., 2017; Martinez-Navarro et al., 2018).”

“PAG could exert a dual control, including inhibition and facilitation, on nociceptive transmission in the dorsal horn and trigeminal nucleus [8] by descending PAG-RVM (rostral ventromedial medulla) pathway contributing to central sensitization and development of secondary hyperalgesia [8, 9].”