Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla

Heinricher, Mary M.; Morgan, Michael M.; Tortorici, Vı́ctor

doi:10.1016/0306-4522(94)90022-1

Cited by 240 publications

(148 citation statements)

References 44 publications

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“…These results provide evidence for the hypothesis that opioid-induced antinociception in the VLO might be produced by opioid via the mu opioid receptor subtype 1, which exerts inhibitory effects on GABAergic inhibitory neurons, resulting in disinhibition of VLO projection neurons and leading to activation of the VLO-PAG brainstem descending pain control system to depress the nociceptive inputs at the trigeminal/spinal cord level. A similar disinhibitory effect has been found in the rostral ventral medulla [93] . In summary, there exists one feedback nociceptive pathway, consisting of spinal cord/trigeminal-Sm-VLO-PAGtrigeminal/spinal cord, that is regulated by opioidergic, serotoninergic and GABAergic components and interactive mechanisms (Figure 2).…”

Section: Neurotransmitter and Receptor Mechanisms Underlying Vlo Invosupporting

confidence: 80%

Cerebral cortex modulation of pain

2008

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Pain is a complex experience encompassing sensory-discriminative, affective-motivational and cognitiv e-emotional components mediated by different mechanisms. Contrary to the traditional view that the cerebral cortex is not involved in pain perception, an extensive cortical network associated with pain processing has been revealed using multiple methods over the past decades. This network consistently includes, at least, the anterior cingulate cortex, the agranular insular cortex, the primary (SΙ) and secondary somatosensory (SΠ) cortices, the ventrolateral orbital cortex and the motor cortex. These cortical structures constitute the medial and lateral pain systems, the nucleus submedius-ventrolateral orbital cortex-periaqueductal gray system and motor cortex system, respectively. Multiple neurotransmitters, including opioid, glutamate, GABA and dopamine, are involved in the modulation of pain by these cortical structures. In addition, glial cells may also be involved in cortical modulation of pain and serve as one target for pain management research. This review discusses recent studies of pain modulation by these cerebral cortical structures in animals and human.

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Section: Neurotransmitter and Receptor Mechanisms Underlying Vlo Invosupporting

confidence: 80%

Cerebral cortex modulation of pain

2008

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“…Tonic activity in an opposing cell population, ON cells, is thought to produce a state of hyperalgesia (Heinricher et al, 1989;Porreca et al, 2002). Tonic excitation of OFF cells and inhibition of ON cells in response to various opioids administered by different routes techniques are consistent, often replicated, findings in anesthetized rats (Toda, 1982;Heinricher and Rosenfeld, 1985;Barbaro et al, 1986;Fang et al, 1989;Heinricher et al, 1992Heinricher et al, , 1994Brink et al, 2006;Hellman et al, 2007). However, a single study in the unanesthetized rat did not observe any change in tonic ON cell activity in response to morphine as is observed in anesthetized rats (Martin et al, 1992).…”

Section: Introductionmentioning

confidence: 75%

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Hellman

Mason

2012

J. Neurosci.

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In anesthetized rats, opioid analgesia is accompanied by a specific pattern of tonic activity in two neuronal populations within the medullary raphe magnus (RM): opioids silence pain-facilitatory ON cells and produce sustained discharge in pain-inhibitory OFF cells. These tonic activity patterns, hypothesized to generate a tonic analgesic state, have not been observed in recordings made without anesthesia. Therefore, we recorded ON and OFF cell activity before and after an analgesic dose of morphine in unanesthetized mice. The tonic activity of ON and OFF cells was unchanged by morphine. Rather, morphine suppressed the phasic ON cell excitation and OFF cell inhibition evoked by noxious stimulation. Before morphine, the magnitude of the noxious stimulus-evoked burst in ON cells correlated with motor withdrawal magnitude, suggesting that ON cells facilitate nocifensive motor reactions. Contrary to model prediction, OFF cell activity was greater before stimulus trials that evoked withdrawals than those without withdrawals. Since withdrawals only occurred when OFF cell activity was suppressed, a decrease in OFF cell activity appears to serve as a pro-nociceptive signal that synchronizes and therefore strengthens the ensuing motor reaction. We further propose that morphine acts in RM to suppress ON and OFF cell phasic responses and thereby disable RM's pro-nociceptive output. Thus, RM cells produce antinociception by failing to exert the pronociceptive effects normally engaged by noxious stimulation. These findings revise the conventional understanding of supraspinal opioid analgesia and demonstrate that RM produces on demand rather than state modulation, allowing RM cells to serve other functions during pain-free periods.

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“…Neurons in the PAG relay information to brainstem regions such as the RVM, the parabrachial nucleus, and the nucleus tractus solitarius (Lewis et al, 1987;Thurston and Randich, 1992;Yoshida et al, 1997). The RVM inhibits efferent nociceptive transmission at the spinal cord (Fields and Heinricher, 1985;Heinricher et al, 1989) through opioid dependent mechanisms (Heinricher et al, 1994). The brainstem regions such as the RVM project to the dorsal horn of the spinal cord from which a relay to the primary afferent nerve terminals elicits the final phase of inhibition of nociception during SIA.…”

Section: Brainstemmentioning

confidence: 99%

Stress-induced analgesia

Butler

Finn

2009

Progress in Neurobiology

545

442

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Abbreviations: SIA, stress-induced analgesia; FCA, fear-conditioned analgesia; GABA, Ȗ-aminobutyric acid; HA, high analgesia; LA, low analgesia; fMRI, functional magnetic resonance imaging; DNIC, diffuse noxious inhibitory control; PAG, periaqueductal grey; RVM, rostroventral medulla; 5-HT, 5-hydroxytryptamine; CB 1 , cannabinoid type 1; CB 2 , cannabinoid type 2; NMDA, N-methyl-D-aspartic acid; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mGluR, metabotropic glutamate receptor; NK1, neurokinin 1; SP, substance P; 2-AG, 2-arachidonoylglycerol; FAAH, fatty acid amide hydrolase; MGL, monoacylglycerol lipase; HPA, hypothalamo-pituitary-adrenal; ACTH, adrenocorticotropic hormone 3 ABSTRACT For over 30 years, scientists have been investigating the phenomenon of pain suppression upon exposure to unconditioned or conditioned stressful stimuli, commonly known as stress-induced analgesia. These studies have revealed that individual sensitivity to stressinduced analgesia can vary greatly and that this sensitivity is coupled to many different phenotypes including the degree of opioid sensitivity and startle response. Furthermore, stress-induced analgesia sensitivity can vary a great deal depending on age, gender, and prior experience to stressful, painful, or other environmental stimuli. Stress-induced analgesia is mediated by activation of the descending inhibitory pain pathway.Pharmacological and neurochemical studies have demonstrated involvement of a large number of neurotransmitters and neuropeptides. In particular, there are key roles for the HQGRJHQRXV RSLRLG PRQRDPLQH FDQQDELQRLG Ȗ-aminobutyric acid and glutamate systems. The study of stress-induced analgesia has enhanced our understanding of the fundamental physiology of pain and stress and has been a useful approach for uncovering new therapeutic targets for the treatment of pain and stress-related disorders.4

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Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla

Cited by 240 publications

References 44 publications

Cerebral cortex modulation of pain

Cerebral cortex modulation of pain

Opioids Disrupt Pro-Nociceptive Modulation Mediated by Raphe Magnus

Stress-induced analgesia

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