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”

“There is also thought to be state-dependent and bidirectional control of pain modulation through serotonergic projections from the RVM to the TCC that is distinct to “ON” and “OFF” cells (269).”

“Descending opioid-dependent pain modulation pathways are also engaged by other behavioural and motivational states, including vigilance and fea”

“…example, ascending interoceptive signals bring sensory prediction errors from the internal milieu to the brain via lamina I and vagal afferent pathways, and they are anatomically positioned to be modulated by descending visceromotor predictions that control the internal milieu (e.g. Fields, 2004).”

“They also have found that these reductions are accompanied by increases in neural activity within brain areas known to be involved in emotional regulation (Fields 2004, Petrovic et al. 2005, Zubieta et al. 2001).”

“…example, ascending interoceptive signals bring sensory prediction errors from the internal milieu to the brain via lamina I and vagal afferent pathways, and they are anatomically positioned to be modulated by descending visceromotor predictions that control the internal milieu (e.g. Fields, 2004).”

“The amygdala modulates pain perception through direct connections with the descending pain inhibitory syste”

“The gate control theory posits and much subsequent work on central regulation of pain has shown that the periaqueductal gray (PAG) exerts central control over spinal pain pathways (Melzack and Wall, 1965; Fields, 2004).”

“opioid receptors on the presynaptic terminals of primary nociceptive neurons and spinal cord resident neurons [38].”

“In addition to its tissue-protective role, pain provides a teaching signal that enables individuals to avoid future harm (Apkarian et al., 2009; Johansen and Fields, 2004).”

“The RVM (as well as the PAG) is characterized by distinctive cells (Fields et al., 1983; Heinricher et al., 1987) that show a pause of firing (Off cells) or a burst of firing (On cells) just before a nociceptive withdrawal reflex occurs in the anesthetized animal (Fields, 2004; but see Mason, 2012).”

“Indeed, endogenous opioids play a central role in analgesia and the perception of painful stimuli (Fields, 2004).”

“This illustrates a critical issue in our understanding of pain relief as an affective and motivational stat”

“38 Fields H. State-dependent opioid control of pain. Nat. Rev. Neurosci. 5(7), 565–575 (2004).”

“This may explain why we did not observe cue effects on the PAG, a PPN region critical for endogenous opioid-based analgesia (Fields, 2004) that is modulated by placebo (Wager et al.”

“Notably, although a role of the PAG in descending pain inhibition is well established (Millan, 2002), there is also evidence from animal studies for pronociceptive effects of the PAG under certain contexts such as stress (Fields, 2004; Lovick, 2008).”

“One possible mechanism for the modulatory effect of expectancy on pain is that it activates descending modulatory systems (Fields, 2004; Fields et al., 2006).”

“For instance, under great emotion or intense concentration, people often report few signs of pain despite severe injuries (Fields, 2004).”

“Whereas spinal adaptive mechanisms are important in chronic pain, our study focused on the brainstem nucleus raphe magnus (NRM), a crucial supraspinal site for maintenance of pain hypersensitivity in behavioral states of chronic pai”

“Bottom image: shows activation in right anterior insula (46, 20, 4), and C shows activation in bilateral rostral anterior cingulate cortex (2, 44, 10).”

“The reinforcing consequences of terminating an aversive event are widely appreciated (Craig, 2003; Fields, 2004; Kim et al., 2006; Seymour et al., 2005).”

“Using the same region as seed for the present connectivity fMRI analysis, we found that healthy controls displayed higher rACC connectivity than FM patients to the hippocampus, a cluster that extended into the PAG area of the brainstem.”

“Mean values of pain ratings and SEMs were as follows: interictal patients, 6.7 2.3; preictal patients, 6.2 3.4; ictal patients, 6.5 2.3; controls, 6.5 2.4 (Table 1).”

“…descending pain inhibitory pathway (Fields, 2004; Kong et al., 2010a), involving the rostral and pregenual anterior cingulate cortex (pgACC), the periaqueductal gray, the parahippocampal area, hypothalamus, and rostral ventromedial brainstem (Fields, 2004; Kong et al., 2010a; Eippert et al., 2009).”

“Copyright (cid:1) 2016 by the International Association for the Study of Pain.”

“There is a well-established relationship between pain perception and endogenous opioids (Urban and Gebhart, 1999; Fields, 2004; Przewlocki and Przewlocka 2001).”

“This finding implies that these areas play an important role in opioidergically mediated pain regulation (20).”

“The study by Pessiglione et al. showed that even when participants are unable to report how much money is at stake, they still use more effort in terms of force for higher amounts of money.”

“These nuisance signals are typically adjusted for in resting-state FC studies because they reflect signal fluctuations of nonneuronal origin (e.g., physiological artifacts associated with variables such as cardiac and respiratory cycles, CSF motion, and scanner drift) (Fox and Raichle, 2007).”

“Since the rACC is a key region for descending inhibition of pain (43, 44), the lower rACC coherence in FM patients provides support for the hypothesis that the FM pathology may be associated with dysfunction of descending pain modulation (36, 45, 46).”

“While neutral cells and 5-HT like cells have only been partially characterized, more is understood about the firing patterns of ON and OFF cells (Fields, 2004).”

“Subsequently, all sections were processed according to the following steps: (1) post-fixation with glutaraldehyde, (2) silver enhancement using the HQ Silver Kit (Nanoprobes, Stony Brook, NY, USA), (3) incubation with the ABC kit (Vector), (4) reaction with DAB tetrahydrochloride and H2O2, (5) osmification, and (6) co…”

“This phylogenetically highly conserved network is anatomically well-suited to mediate between higher-order brain processes and the spinal cord level through dorsal horn facilitation or inhibition [28, 29].”

“a direct response to noxious stimuli might otherwise disrupt other adaptive responses [89].”

“In RVM, ON and OFF cells fire on nociceptive stimulus onset and offset, and are thought to be associated with pain facilitation and suppression, respectively(Fields, 2004).”

“…medulla, and locus ceruleus) from which descending pain-modulating pathways originate and in the dorsal horn region of the spinal cord, an area important for the relay of nociceptive input to the brain and a primary site of action for the analgesic effects of opioids (Fields, 2004; Fig.”

“Similarly, the utility and consequently the hedonic experience of interpersonal touch largely depends on the context and internal needs and motivational goals.”

“R I J a b c d e a A R R A A K P P P f R F 1 u a c r t P w [ t m r i [ t a b p T 0 d Behavioural Brain Research 211 (2010) 215–219 Contents lists available at ScienceDirect Behavioural Brain Research journa l homepage: www.e lsev ier .com/ locate /bbr esearch report ntrinsic functional connectivity of the periaqueducta…”

“The pgACC is part of the descending pain-modulating antinociceptive system, which also involves other areas such as the periaqueductal gray, the parahippocampal area, anterior insula, hypothalamus and rostral ventromedial brainstem (6,11,69).”

“The brainstem/medulla [17,21] is another important region in the descending pain modulatory network, which sends direct projections to dorsal horn laminae to modulate pain transmission.”

“modulation [25,50,65,68] and is anatomically substantiated by a thoroughly described descending pain-modulating pathway [26].”

“Similar cognitive processes are involved in the placebo mechanism [14].”

“All three of these factors vary according to the neuronal pathways involved and the type of stimulatio”

“medulla where OFF and ON cells that respectively mediate descending inhibition and facilitation have been identified.(29) The motivation-decision model of Fields has suggested a contextdependent activation of these cells that guide the behavioral outcome of a nociceptive stimulus.”

“The PAG is a key region in the top-down control of pain transmission in the spinal cord through influences on the medulla (Fields, 2004; Wager, 2005a).”

“The high concentration of opioid receptors expressed in rACC (Vogt et al., 1993; Fields, 2004) has been hypothesized to relate to attentional mechanisms that can suppress pain processing (Petrovic et al., 2002), a suggestion that has received experimental support (Zubieta et al., 2005; Wager et…”

“These receptors are localized in subcortical regions of the brain, as previously mentioned, from which the descending pain pathways originate, such as in the thalamus, the PAG and the RVM, as well as in the spinal cord’s dorsal horn [85].”

“and adenosine A1 receptor agonists, have been found to reduce ON cell and stimulate OFF cell activity after intra-PAG injections (Fields et al., 1983; Heinricher and Tortorici, 1994; Meng et al., 1998; Fields, 2004; de Novellis et al., 2005; Maione et al., 2007).”

“Of these, the RVM is the principal relay in the integration of ascending nociceptive inputs with descending outputs from rostral sites (Fields, 2004; Fields et al., 2005), as well as the major source of bulbospinal projections that terminate in laminas I, II and V of the dorsal horn, mostly via OFF…”

“Since the function of the DPMS is state dependent, we hypothesised that this state change would be reflected in alterations in the connectivity pattern of the DPMS, specifically the periacqueductal grey (PAG) [18,19].”

“either facilitate (ON cells) or inhibit (OFF cells) dorsal horn responses to noxious stimulation.(15) Although prediction-based facilitation of nociceptive transmission has not been extensively studied in human subjects, we demonstrated using functional magnetic resonance imaging that there is relative activation in t…”

“Since the original report that electrical stimulation of the midbrain produces profound analgesia (Reynolds, 1969), much attention has been focused on descending control systems, which can influence the spinal transmission of noxious inputs (Millan, 2002; Fields, 2004).”

“While it is well established that endogenous opioids play a key role in modulating these systems [44,175], emerging research implicates central dopamine (DA) signaling as another important”

“Indeed, endogenous opioid secretion is considered as part of a defensive reaction to inescapable stress conditions, including pain (Vaccarino et al., 1999; Fields, 2004) that depends on pain intensity independent of its aetiology or lesion site, and should therefore have occurred in both peripheral and central pain (a…”

“Opioid peptides, including β-endorphin, enkephalins and dynorphins are expressed in neurons in pain-relevant regions of the central or peripheral nervous system as well as in immune cells accumulating in peripheral painful tissue (Fields, 2004; Stein and Machelska, 2011).”

“first-order primary afferent neurons, second-order neurons in the spinal cord, and brain where pain messages are integrated, and descending inhibitory pain pathways recruiting periaqueductal gray and rostral ventral medulla systems [16,17].”

“A third pathway, namely the descending pain inhibitory pathway, balances the two ascending pain pathways (25, 26, 56, 57).”

“The cellular mechanisms underlying the analgesic and hyperalgesic effects of manipulating inhibitory and excitatory neurotransmission in the vlPAG have not been directly evaluated (Moreau and Fields, 1986; Carstens et al., 1988; Jacquet, 1988; Sandkühler et al., 1989; Vaughan et al., 1997; Budai and Fields, 1998; Fiel…”

“The ACC contains a high concentration of opioid receptors [48], and has been regarded as a functional region in opioid analgesia and in other forms of pain modulation [49,50], which may suggest a similar involvement of higher order control of opioid-dependent placebo analgesia.”

“The decrease in GABA release promotes disinhibition of the OFF nociceptive neurons and direct inhibition of ON cells, resulting in antinociception (for reviews, see Fields 2004; Rea et al. 2007; Palazzo et al. 2010; Fig.”

“, 2009a), and given its bidirectional control of pain modulation (Fields, 2004), it is probably also engaged in nocebo hyperalgesia.”