Evaluation of the periaqueductal central gray (PAG) as a morphine-specific locus of action and examination of morphine-induced and stimulation-produced analgesia at coincident PAG loci

Lewis, Vahn A.; Gebhart, G. F.

doi:10.1016/0006-8993(77)90886-1

Cited by 237 publications

(58 citation statements)

References 59 publications

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“…Next, we examined the sensitivity of wild-type (LTS-positive) and α1G −/− (LTS-negative) GABAergic neurons to the endogenous opioid neurotransmitter [met 5 ]-enkephalin (ME) based on the results in Fig. 3, because ME is known to be released by stress in vivo and inhibit neurons mostly through μORs (4,5,21,22). After recording basal discharge activity, we applied ME (30 μM) to wild-type low threshold-spiking GABAergic neurons.…”

Section: Deletion Of Lts In μOr-positive Gabaergic Neurons Results Inmentioning

confidence: 99%

T-type channels control the opioidergic descending analgesia at the low threshold-spiking GABAergic neurons in the periaqueductal gray

Park

Kim

Yoon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Endogenous opioids generate analgesic signals in the periaqueductal gray (PAG). However, because cell types in the PAG are difficult to identify, its neuronal mechanism has remained poorly understood. To address this issue, we characterized PAG neurons by their electrical properties using differentially labeled GABAergic and output neurons in the PAG. We found that GABAergic neurons were mostly fast-spiking cells and could be further divided into two distinct classes: with or without low-threshold spikes (LTS) driven by T-type channels. In contrast, the PAG output neurons lacked LTS and showed heterogeneous firing patterns. To reveal the function of the LTS, we examined the mutant mice lacking the α1G T-type channels (α1G). The mutant mice lacked LTS in the fast-spiking GABAergic neurons of the PAG and unexpectedly showed impaired opioid-dependent analgesia; a similar phenotype was reproduced in PAG-specific α1G-knockdown mice. Electrophysiological analyses revealed functional expression of μ-opioid receptors in the low threshold-spiking GABAergic neurons. These neurons in the mutant lacking LTS showed markedly enhanced discharge activities, which led to an augmented inhibition of output neurons. Furthermore, the impaired analgesia observed in α1G −/− mice was reversed by blocking local GABA A receptors. These results indicate that α1G T-type channels are critical for the opioidergic descending analgesia system in the PAG.opioid-descending analgesia | α1G | morphine | stress | calcium-activated potassium channel | afterhyperpolarization

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Section: Deletion Of Lts In μOr-positive Gabaergic Neurons Results Inmentioning

confidence: 99%

T-type channels control the opioidergic descending analgesia at the low threshold-spiking GABAergic neurons in the periaqueductal gray

Park

Kim

Yoon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…microinjection (22)(23)(24)(25)(26). Both stimulation-produced antinociception (SPA) and antinociception from morphine microinjection into supraspinal loci are reversed by naloxone, further implicating the activation of endogenous opioidergic systems in these phenomena (27).…”

Section: Figurementioning

confidence: 99%

Central modulation of pain

Ossipov¹,

Dussor²,

Porreca³

2010

J. Clin. Invest.

894

728

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It has long been appreciated that the experience of pain is highly variable between individuals. Pain results from activation of sensory receptors specialized to detect actual or impending tissue damage (i.e., nociceptors). However, a direct correlation between activation of nociceptors and the sensory experience of pain is not always apparent. Even in cases in which the severity of injury appears similar, individual pain experiences may vary dramatically. Emotional state, degree of anxiety, attention and distraction, past experiences, memories, and many other factors can either enhance or diminish the pain experience. Here, we review evidence for "top-down" modulatory circuits that profoundly change the sensory experience of pain.

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“…Opioid administration into the PAG in the rat [24,25,31,34,53] and cat [41], as well as electrical stimulation of the PAG in humans [23] produces antinociception. This antinociception can be attenuated by concurrent administration of an opioid antagonist such as naloxone [1,17,26], indicating that antinociception evoked from the PAG is opioid receptor-mediated.…”

Section: Introductionmentioning

confidence: 99%

PAG mu opioid receptor activation underlies sex differences in morphine antinociception

Bernal

Morgan

Craft

2007

Behavioural Brain Research

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Given the findings that (1) systemic opioid antinociception varies by estrous stage in females, and (2) the magnitude of sex differences in opioid antinociception is negatively correlated with opioid agonist efficacy, we hypothesized that sex differences in the function of the descending pain modulatory system are likely influenced by estrous stage in females and by the number of available opioid receptors therein. The present study tested these hypotheses by (1) comparing antinociception produced by morphine microinjection to the ventral periaqueductal gray (vPAG) in females at different stages of the estrous cycle, and (2) examining systemic morphine antinociception in males vs. females under conditions of reduced vPAG mu opioid receptor availability. When estrous stage of females was not controlled for (Experiment 1), there was no significant sex difference in tail withdrawal antinociception following morphine microinjection (0.3-10 μg), although morphine was more potent in males than females in producing immobility. Experiment 2 showed that intra-vPAG morphine produced less antinociception and immobility in estrus than in diestrus females; that is, only estrus females' response to morphine was lower than that of males. Experiment 3 showed that microinjection of the irreversible mu opioid antagonist β-funaltrexamine (β-FNA) into the vPAG shifted the systemic morphine dose-effect curve farther to the right in females than in males. That is, a reduction in available vPAG mu opioid receptors had a greater impact on opioid antinociception in females than in males, suggesting that females have fewer vPAG mu opioid receptors than males. Overall, these data suggest that ovarian hormones and PAG mu opioid receptor density contribute to sex differences in antinociception produced by morphine.

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Evaluation of the periaqueductal central gray (PAG) as a morphine-specific locus of action and examination of morphine-induced and stimulation-produced analgesia at coincident PAG loci

Cited by 237 publications

References 59 publications

T-type channels control the opioidergic descending analgesia at the low threshold-spiking GABAergic neurons in the periaqueductal gray

T-type channels control the opioidergic descending analgesia at the low threshold-spiking GABAergic neurons in the periaqueductal gray

Central modulation of pain

PAG mu opioid receptor activation underlies sex differences in morphine antinociception

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