Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial scratching

doi:10.1016/0006-8993(95)00871-M

Brain Research

Volume 695, Issue 2, 16 October 1995, Pages 267-270

https://doi.org/10.1016/0006-8993(95)00871-M Get rights and content

Abstract

It has been proposed that opioids act at the level of the medulla to produce facial pruritus. Supporting this hypothesis, microinjection of μ-opioid receptor agonists into the medullary dorsal horn (MDH; trigeminal subnucleus caudalis) of monkeys produces facial scratching behavior. The present study sought to establish a rodent model of opioid-induced facial pruritus. To this end, morphine (0.1, 0.3 or 1.0 μg/0.2 μl) or saline (0.2 μl) was unilaterally microinjected into the MDH of male Sprague-Dawley rats. Behavior for the 20 min preceding and the 80 min after this microinjection was videotaped. Morphine produced dose-dependent increases in facial scratching behavior ipsilateral to the microinjections with the peak effect at 30–40 min after microinjection. Facial scratching continued for the entire 80 min post-microinjection test period. Morphine also produced a lesser degree of facial scratching contralateral to the microinjections. Increases in facial scratching ipsilateral to the microinjection of 0.3 μg morphine into the MDH were attenuated by 0.4 mg/kg s.c. naloxone. These findings support the hypothesis that the MDH is a critical site of action of opioid agonists in producing facial pruritus.

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Human beings experience intense pruritus in association with intrathecal morphine and other compounds with affinity for the mu opioid receptor [5,6]. Non-human primates exhibit scratching behavior in association with the central administration of mu agonist ligands, behavior prevented by kappa receptor stimulation [9,23,64]. These important findings in part, have supported the development of drugs with kappa agonist activity to treat pruritus in patients with liver disease [5].
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In this manuscript, the author provides an interpretation of data that have evolved over the past few years, and expands the hypothesis stating that the endogenous opioid system contributes to the pruritus of cholestasis. There is strong evidence to support a role of the endogenous opioid system in the mediation of pruritus of central origin: (i) the administration of morphine intrathecally to human beings is associated with pruritus, which is ameliorated and which can be prevented by opiate antagonists [13,14], (ii) in laboratory animals, the central administration of morphine and other agonists at the mu opioid receptor is associated with scratching behavior, which is decreased and also prevented by opiate antagonists [15–17]. Thus, stimulation of opioid receptors, mostly the mu opioid receptor, is associated with pruritus and scratching behavior.
The pruritus of cholestasis is a maddening complication of liver disease. Increased opioidergic tone contributes to the pruritus of cholestasis, as evidenced by the amelioration of the symptom by opiate antagonists. Obeticholic acid, an agonist of the farnesoid receptor, has been approved for the treatment of primary biliary cholangitis, a disease characterized by cholestasis; this drug is associated with pruritus, the cause of which is unknown. In animal models, bile acids, which accumulate in the body as a result of cholestasis, have been reported to cause scratching behavior mediated by the TGR5 receptor, in an opioid-dependent manner, in laboratory animals. As obeticholic acid also binds to TGR5, the pruritus caused by this drug is likely to be mediated by the opioid system. Lisophosphatidic acid, which has been reported to be increased in patients with cholestasis and pruritus, has been described to cause scratching behavior that is prevented by an opiate antagonist in laboratory animals, suggesting an opioid-receptor mediated mechanism of scratching. In summary, evidence continues to support a role of the endogenous opioid system in the pathogenesis of the pruritus of cholestasis
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At the concentrations tested, morphine did not affect grooming in the study by Lee et al. It has also been shown that injection of morphine within the spinal trigeminal nucleus causes a robust increase in facial scratching in rats (Thomas and Hammond, 1995). The area of the spinal trigeminal nucleus which was injected by Thomas and Hammond (1995) corresponds to the level of the brainstem/spinal cord targeted by intracisternal injections in our study.
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The reduction of incidence of pruritus is the major benefit of combining morphine and nalbuphine in PCA. Opioid-related pruritus derives from agonism at the mu-opioid receptor.20 21 Nalbuphine does not induce pruritus and it can antagonize morphine-related pruritus.3
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Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial scratching

Abstract

Pain

Gastroenterology

J. Invest. Dermatol.

Lancet

Peptides

Brain Res.

Brain Res.

Management of the pruritus of cholestatis: potential role of opiate antagonists

Am. J. Gastroenterol.

Intrathecal and epidural administration of opioids

Anesthesiology