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”

“The theory is that cognitive expectations maintained in prefrontal cortex may activate the PAG, which has the capability to inhibit pain signals at the level of the spinal cord (e.g., Fields, 2004).”

“The ACC also projects to the periaqueductal grey, an area that plays an important role in descending modulation of pain (Wyss and Sripanidkulchai 1984; Fields 2004).”

“The amygdala is also believed to be a key substrate of the reciprocal relationship between pain and affective states and disorders such as anxiety [3,10,12,13].”

“…apparent in the pgACC/rACC and the periacqueductal gray, two brain regions that have been linked with endogenous opioid release in animal models (Fields 2000, 2004) and in prior studies of placebo analgesia in humans (Levine et al. 1978) (Eippert et al. 2009a; Wager et al. 2007b; Zubieta et al.…”

“We hypothesized that morphine should activate regions of the brain associated with each of its well described behavioral effects, including analgesia (4), reward/addiction (5), and sedation (6).”

“Opioids, such as morphine, are the mainstay for the treatment of moderate to severe pain (Fields, 2004).”

“For example, recent studies have clarified the involvement of opioid and nonopioid mechanisms in placebo analgesia; the relationship between placebos, conditioning, and immunosuppression; and neuroanatomy substrates associated with placebo responding [7–11].”

“In general, their primary function has been viewed primarily as gain control, reducing the rostral flow of nociceptive information to facilitate escape, feeding, or mating in the presence of pain or to amplify nociceptive information during disease or injury (Millan, 2002; Fields, 2004).”

“affective lives? Neurosci Biobehav Rev 35(9):1791–1804.”

“McGaraughty S, Heinricher MM (2002) Microinjection of morphine into various amygdaloid nuclei differentially affects nociceptive responsiveness and RVM neuronal activity.”

“The notion that analgesia is rewarding is supported by several lines of evidence: termination of a painful stimulus can be rewarding (Seymour et al., 2005) and, depending on the state of the organism, endogenous opioids can modulate reward systems (reviewed in (Fields, 2004)).”

“Thus, the effects of the emotional state of the animal may modulate perceived sensations from peripheral organs, completing a loop that may be modulated by both central and peripheral neural activity.(143) Hormonal.”

“Opioids also regulate descending inhibitory pain pathways by recruiting receptors in periacqueductal grey and rostral ventral medulla [5,6].”

“4) The amygdala is emerging as a neuronal interface between pain and affective states and disorders such as anxiety (Fields 2004; Heinricher and McGaraughty 1999; Neugebauer et al. 2004; Neugebauer 2006; Pedersen et al. 2007; Rhudy and Meagher 2001).”

“High activity in these regions also predicted lower levels of sadness and feelings of rejection (Hsu et al., 2013), perhaps analogous to a coping mechanism for physical pain that is activated in stressful or threatening contexts (Fields, 2004).”

“In the RVM, OFF cells are tonically inhibited by ON cells via GABAergic mechanisms (Fields, 2004).”

“That said, it needs to be acknowledged that most evidence stems from animal research (Fields, 2004) and that the precise mapping of these pathways in humans is currently unknown.”

“These differences in opioid receptor availability in turn would likely influence responses to opioid analgesics.(38)”

“Descending modulatory pathways can also facilitate pain perception in certain cases (Fields, 2004).”

“Both serotonergic and dopaminergic systems have important roles in pain processing – including pain modulation (serotonin) (Fields, 2004; Benarroch, 2008) and”

“Two types of neuron in the RVM, known as on and off cells, have been described as facilitating or inhibiting nociceptive transmission (Fields, 2004).”

“The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are critical components of a supraspinal opioidergic circuit (SOC) that modulates pain, the subjective experience frequently linked to nociception [6,7,33,49].”

“Furthermore, a previous study had discovered that RVM pronociceptive ON-cells express the μ-opioid receptor (MOR) (40).”

“This influence of vmPFC–PAG coupling on sensory processing may potentially reflect a descending modulatory mechanism acting at the spinal cord level, facilitating “positive” touch signals and suppressing nociceptive signals (7, 41).”

“Placebo analgesia requires the dynamic, context-dependent communication between cortical and subcortical structures known to be involved in descending pain inhibition [25,44].”

“Placebo treatments in humans were initially hypothesized to be associated with the activity of mesolimbic DA cells during reward anticipation and their capacity to adapt to environmental information (Fields, 2004; Irizarry and Licinio, 2005).”

“Indeed, one of the main challenges of these endogenous systems is to understand their function and meaning [12].”

“Chronic inflammation alters supraspinal pain-controlling sites (Przewlocki & Przewlocka, 2001; Tsuruoka et al., 2003) and activates descending opioidergic paincontrolling pathways (Fraser et al., 2000; Fields, 2004), which in turn impacts on pain perception.”

“It also means that both systems can be activated at the same time to varying degrees, and by implication, that the total inhibitory effect of opioids depends on the level of facilitatory influence [14].”

“RVM is a key region of the descending pain modulatory system (Millan, 2002; Fields, 2004; Kong et al., 2010), while TCC comprises the second-order neurons of the trigeminovascular nociceptive pathway.”

“Stimulation of BLA–CeA projection induces reward-like effect As pain causes aversive and unpleasant experience, pain inhibition is rewarding by inducing negative reinforcement (Fields, 2004).”

“0 through the descending pathway from the rostroventral medulla [23,44].”

“They serve to shift the motivational state of individuals towards the display of behaviors associated with coping with either actual or potential threats and away from the expression of nondefensive behaviors (Kavaliers and Choleris 2001; Fields 2004 ).”

“, 2007) coupled with morphine's well-characterized ability to inhibit nociceptive signaling (Fields, 2004; McCabe et al., 2014).”

“The mutual interplay between bottom-up and top-down signaling therefore represents a fundamental dimension in pain processing (Fields, 2004; Heinricher et al., 2009).”

“In these various contexts the induction of analgesia facilitates the expression of behaviors appropriate to particular situations (e.g. escape from predators, ingestion of food) and the inhibition of inappropriate behaviors and responses (Fields, 2004).”

“We therefore investigated whether the control group would show enhanced processing in a network implicated in descending pain control (Harris, 1996; Bingel et al., 2006) comprising the rACC, the amygdala, the PAG, and the RVM. Critically, if this network is indeed opioidergic and engaged by conditioning, then (1) proc…”

“The rostral ventromedial medulla (RVM), consisting of the nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis and gigantocellularis pars alpha, is a key brainstem structure that relays processed information of pain from higher brain sites and exerts powerful descending modulation of spinal pain transmiss…”

“However, in most cases, DOP-receptor-selective agonists produce only weak analgesic effects [ 9 ,41].”

“…morphine on AC expression levels and, consequently, on cAMP-mediated synaptic actions and pain behaviors, focusing on neurons in the nucleus raphe magnus (NRM), a brainstem site critically involved in opioid modulation of pain transmission in the spinal cord (Scholz and Woolf, 2002; Fields, 2004).”

“administration of opioids or cannabinoids, which are able to inhibit nociception, inhibits ON cells and increases OFF cells activity.(12,21,23,28) Thus, changes in ON and OFF cells activity are predictive of pain response modulation for putative analgesic drugs.”

“-opioid receptor activation of descending pain control circuits depends on opioid inhibition of GABAergic neurotransmission within the PAG (Fields, 2004).”

“The PAG in the mesencephalon – one of the main supraspinal centers for the processing of nociceptive impulses from muscle – is also the site of origin of descending pain-modulating pathways (Fields 2004).”

“The failure of opioid antagonists to inhibit AAK1 inhibitor antinociception shows that AAK1 antinociception does not use the opioid system, a major inhibitory pain pathway used by endogenous and exogenous antinociceptives (Fields, 2004).”

“The PAG was chosen for analysis because: 1) it is well known that the PAG plays a role in pain modulation [48-52]; 2) PAG has been found to play an important role in acupuncture analgesia [53-55]; and 3) in a previous analysis conducted using this same data set, we found that fMRI signal change to calibrated heat pain…”

“In addition, connectivity of PAG, which is a major opioid-sensitive pain-modulatory structure in both rodents (14, 22) and humans (23) and is engaged in aversive learning (24), appeared entirely remodeled in mutant mice (Fig.”

“The principle of circuit flexibility relying on connectivity modulation also extends to vertebrates as exemplified by stress-induced analgesia, an acute suppression of pain generated mediated by opioids (151, 157, 158).”

“…thought to receive projections from the hypothal‐ amus and the limbic forebrain, including from several regions of the frontal neocortex and amygdala (Campos & Guimarães, 2009; Fogaça, Aguiar, Moreira, & Guimarães, 2012; Lisboa, Resstel, Aguiar, & Guimarães, 2008; for a review, see Fields, 2004).”

“The classical opioid system modulates many different aspects of physiology but is most well known for its control of nociception (Fields 2004) and reward-related behavior (Nestler 2004).”

“This dysfunction also results in an imbalance between excitatory and inhibitory processes, exacer-bating chronic pain 44,45 .”

“Results of experiments using microinjections of -opioid receptor agonists whose analgesic effects were reversed by -opioid receptor antagonists implicate that the -opioid receptor and enkephalins, as endogenous agonists, play a fundamental role in this native endogenous pain control system.(21) Furthermore, the import…”

“There is evidence for both inhibitory and facilitatory serotonergic and non-serotonergic inputs to the dorsal horn [2,10,38,39].”

“the descending pain modulatory system (Eippert and Tracey, 2014; Fields, 2004; Jensen et al., 2012; Kong et al., 2013a; Kucyi et al., 2013; Tracey et al., 2002; Yu et al., 2014a), forming a core network with the PAG and rostral ventral medulla (RVM) (Kong et al.”

“Since acute painful stimuli also raise these CSF levels considerably [170,359,375,400,401], it is fully clear that the central release of β-END forms part of an antinociceptive system controlling pain [71,79,402,403].”

“potential threat, and is advantageous in situations in which a direct response to noxious stimuli might otherwise disrupt other adaptive behavioral responses [91].”

“It is now believed that the PAG receives direct projections from the hypothalamus and regions within the limbic forebrain, such as the ACC.(14,15) It seems likely that these PAG inputs might be the neural basis for forebrain access to the control of bladder emptying and maintenance of social continence.”

“The facilitatory effect of the RVM is exerted by the physiologically characterized ON-cells, while the inhibitory effect is mainly produced by the physiologically characterized OFF-cells [3,5,52,53].”

“…processing level, including food distraction, stabilizes sensory perception in humans and animals by tempering hypervigilant behavior (Aminabadi et al., 2008; Casey and Morrow, 1983; Ford et al., 2008; Hoffman et al., 2008) and potentially modulating mu opioid receptors (Fields, 2004; Mason, 2005).”

“Given the known anatomical and functional connectivity between the PAG and the rostral-ventromedial medulla (Fields, 2004; Millan, 2002; Ossipov et al., 2010) (RVM) we performed an exploratory analysis of the change in [11C]DPN VT in the medulla and the nearby pons and cerebellum.”

“The classic opioid receptor system modulates many different aspects of physiology but is most known for its control of nociception (Fields, 2004) and reward-related behavior (Nestler, 2004).”

“In contrast to MORs, DOR agonists have weak analgesic effects, which, as demonstrated by recent studies, was probably due to none to low levels of surface expression of functional DORs in brain and spinal neurons important in central pain-modulating circuits (Hurley and Hammond, 2000; Fields, 2004; Ma et al., 2006).”

“Indeed, CeA mediates both drug reward-related positive emotional behaviors (Baxter and Murray, 2002; Gottfried et al., 2003; See et al., 2003) and negative emotional states of affective pain (Fields, 2004; Neugebauer et al., 2009).”