Changes in nociception after 6-hydroxydopamine lesions of descending catecholaminergic pathways in mice

Fasmer, Ole Bernt; Berge, Odd‐Geir; Tveiten, Lars; Hole, Kjell

doi:10.1016/0091-3057(86)90207-8

Cited by 25 publications

(15 citation statements)

References 22 publications

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“…We suggest that the present findings help resolve the contradictory results of previous chronic lesion studies of noradrenergic nuclei (13)(14)(15)(16)(17) by showing that altered noradrenergic transmission, whether transitory or chronic, results in a sustained decreased antinociceptive effect of morphine. Because morphine inhibits substance P release in the spinal cord (49), and because NK1-receptor stimulation is essential for the manifestation of the hyperalgesia in Dbh Ϫ/Ϫ mice, the decreased morphine antinociception in these animals was unexpected.…”

Section: Discussioncontrasting

confidence: 40%

“…Although acute lesions or inhibition of noradrenergic spinal afferents produce a state of hyperalgesia and reduced antinociceptive effects of opiates (2,10,12), the increased pain behavior abates over time. In fact, long-term effects of noradrenergic denervation have been reported to result in decreased pain behavior, whereas the antinociceptive effect of morphine is either reduced, unchanged, or increased (13)(14)(15)(16)(17). These conflicting results can be caused in part by the variability in the extent of the removal of noradrenergic neurons or terminals which, when using a neurotoxin, is both incomplete and nonselective.…”

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confidence: 66%

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The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline

Jasmin

Tien

Weinshenker

et al. 2002

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

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Noradrenaline (NA), a key neurotransmitter of the endogenous pain inhibitory system, acutely inhibits nociceptive transmission (including that mediated by substance P), potentiates opioid analgesia, and underlies part of the antinociceptive effects of the widely prescribed tricyclic antidepressants. Lesions of noradrenergic neurons, however, result in either normal or reduced pain behavior and variable changes in morphine antinociception, undermining the proposed association between noradrenaline (NA) deficiency and chronic pain (hyperalgesia). We used mice lacking the gene coding for dopamine ␤-hydroxylase, the enzyme responsible for synthesis of NA from dopamine, to reexamine the consequences of a lack of NA on pain behavior. Here, we show that absence of NA in the central nervous system results in a substance P-mediated chronic hyperalgesia (decreased nociceptive threshold) to thermal, but not mechanical, stimuli and decreased efficacy of morphine. Contrary to studies that show substance P-mediated hyperalgesia requires intense stimuli, we found that even a mild stimulus is sufficient to evoke substance P-dependent hyperalgesia in the NA-deficient mice. Restoring central NA normalized both the nociceptive threshold and morphine efficacy, which is consistent with a tonic inhibitory effect of NA on nociceptive transmission. Unexpectedly, however, antagonists to the substance P receptor (the NK1 receptor) could achieve the same effect as NA replacement. We conclude that when unopposed by NA, substance P acting at the NK1 receptor causes chronic thermal hyperalgesia, and that the reduced opioid efficacy associated with a lack of NA is due to increased NK1-receptor stimulation. N oradrenaline (NA) is an essential neurotransmitter of the endogenous pain inhibitory system (1, 2) that tonically and phasically inhibits spinal nociceptive transmission, including that mediated by substance P (3, 4). By stimulating central nervous system (CNS) ␣ 2 adrenoreceptors, NA increases threshold and latency to noxious stimuli without affecting responses to innocuous stimuli, and potentiates the antinociceptive effects of opiates (5-10).Based on the above understanding, it has been suggested that noradrenergic dysfunction is a key component of certain chronic intractable pain disorders (11). A major caveat is that this hypothesis is based primarily on experimental studies that use acute rather than chronic pain. Although acute lesions or inhibition of noradrenergic spinal afferents produce a state of hyperalgesia and reduced antinociceptive effects of opiates (2, 10, 12), the increased pain behavior abates over time. In fact, long-term effects of noradrenergic denervation have been reported to result in decreased pain behavior, whereas the antinociceptive effect of morphine is either reduced, unchanged, or increased (13-17). These conflicting results can be caused in part by the variability in the extent of the removal of noradrenergic neurons or terminals which, when using a neurotoxin, is both incomplete and nonselective. Moreov...

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Section: Discussioncontrasting

confidence: 40%

mentioning

confidence: 66%

The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline

Jasmin

Tien

Weinshenker

et al. 2002

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

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“…α 2 -AR antagonists decrease tail flick and hot plate latencies in rats (Sagen and Proudfit, 1984), suggesting that adrenergic receptors help set the threshold for thermal nociception. A decreased sensitivity to heat but not to mechanical stimuli was reported in rats and mice following the lesioning of catecholaminergic fibers with 6-OHDA (Fasmer et al , 1986; Kuraishi et al , 1983). Furthermore, Jasmin et al (2002) observed a similar thermal, but not mechanical, hypersensitivity in dopamine β-hydroxylase-KO mice, which lack the enzyme that converts dopamine to NE.…”

Section: Discussionmentioning

confidence: 94%

“…Since co-administration of morphine with NE at the spinal cord results in analgesic synergy (Roerig et al , 1992), we hypothesized that elevated NE levels, due to the loss of feedback inhibition in α 2A -KO, could contribute to the increased spinal morphine efficacy observed in these mice. To test this hypothesis, the toxin 6-OHDA was injected intrathecally to eliminate spinal catecholaminergic fibers that release NE in the spinal cord (Fasmer et al , 1986). In WT mice, morphine efficacy was reduced in mice treated with 6-OHDA compared to mice treated with vehicle, confirming the role of endogenous NE in the antinociceptive effect of morphine (Figure 7A).…”

Section: Resultsmentioning

confidence: 99%

Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors

et al. 2015

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Opioid and α2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co-administered. However, α2-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The α2A-AR subtype is necessary for spinal adrenergic analgesia and synergy with opioids for most agonist combinations. Therefore, we investigated whether spinal opioid antinociception and opioid-adrenergic synergy were under allosteric control of the α2A-AR. Drugs were administered intrathecally in wild type (WT) and α2A-knock-out (KO) mice and antinociception was measured using hot water tail immersion or substance P behavioral assays. The α2A-AR agonist clonidine was less effective in α2A-KO mice in both assays. The absence of the α2A-AR resulted in 10–70-fold increases in the antinociceptive potency of the opioid agonists morphine and DeltII. In contrast, neither morphine nor DeltII synergized with clonidine in α2AKO mice, indicating that the α2AAR has both positive and negative modulatory effects on opioid antinociception. Depletion of descending adrenergic terminals with 6-OHDA resulted in a significant decrease in morphine efficacy in WT but not in α2A-KO mice, suggesting that endogenous norepinephrine acts through the α2A-AR to facilitate morphine antinociception. Based on these findings, we propose a model whereby ligand-occupied versus ligand-free α2A-AR produce distinct patterns of modulation of opioid receptor activation. In this model, agonist-occupied α2A-ARs potentiate opioid analgesia, while non-occupied α2A-ARs inhibit opioid analgesia. Exploiting such interactions between the two receptors could lead to the development of better pharmacological treatments for pain management.

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“…It is plausible, however, that this difference results from differences in the neural anatomical pathways involved in response to these two thermal noxious stimuli. It has been speculated that the animal tail withdrawal response to noxious radiant heat is mediated primarily through a spinal reflex (Grossman et al, 1982;Fasmer et al, 1986;Janss and Gebhart, 1987;Fields, 2004), while the hot plate response is a more "integrated" pain-evoked behavior and mediated primarily through supraspinal sites (Fasmer et al, 1986;Janss and Gebhart, 1987;Picolo et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

High doses of processed Aconiti tuber inhibit the acute but potentiate the chronic antinociception of morphine

Shu

Hayashida

Arita

et al. 2008

Journal of Ethnopharmacology

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Changes in nociception after 6-hydroxydopamine lesions of descending catecholaminergic pathways in mice

Cited by 25 publications

References 22 publications

The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline

The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline

Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors

High doses of processed Aconiti tuber inhibit the acute but potentiate the chronic antinociception of morphine

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