Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats

Shannon, Harlan E.; Lutz, Elizabeth A.

doi:10.1016/s0028-3908(01)00173-3

Cited by 109 publications

(84 citation statements)

References 16 publications

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“…These doses and time courses of β-FNA and nor-BNI have been previously demonstrated to block the activation of μ-and κ-opioid receptors, respectively [26,27]. Additionally, the dose and time course of naltrindole has previously been shown to be ineffective in blocking the analgesic effects of morphine [28]. These results indicate that thermal hyperalgesia in neuropathic pain could be reduced through activation of peripheral δ-opioid receptors.…”

Section: Discussionmentioning

confidence: 71%

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

Shinoda

Hruby

Porreca

2007

Neuroscience Letters

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The possible antihyperalgesic and antiallodynic activity of loperamide, an opioid agonist which does not readily penetrate the blood-brain barrier, were examined in the spinal nerve ligation model of experimental neuropathic pain. Intraperitoneal (i.p.) injection of loperamide effectively reversed thermal hyperalgesia. In contrast, loperamide had minimal effects on cold allodynia and no effects on mechanical allodynia. The antihyperalgesic action of loperamide against noxious heat was antagonized by naltrindole, a δ-opioid receptor selective antagonist, but not by pretreatment with β-funaltrexamine, a μ-opioid receptor selective antagonist, or administration of nor-binaltorphimine, a κ-opioid receptor selective antagonist. Furthermore, i.p. injection of [D-Ala 2 , Glu 4 ]-deltorphin II, a δ-opioid receptor selective peptide agonist, also reversed thermal hyperalgesia. The present results suggest that thermal hyperalgesia in experimental neuropathic pain can be reduced through activation of peripheral δ-opioid receptors. The data suggest the possible application of peripherally restricted and δ-opioid receptor selective agonists in the treatment of some aspects of neuropathic pain without many of the side effects associated with centrally acting opioids and without the peripheral side effects of opioid agonists acting at μ-receptors.

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Section: Discussionmentioning

confidence: 71%

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

Shinoda

Hruby

Porreca

2007

Neuroscience Letters

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“…morphine that produce scratching are smaller than doses of i.c. morphine necessary to produce antinociceptive responses against acute or inflammatory pain in rats Shannon and Lutz, 2002). Large doses of i.t.…”

Section: Discussionmentioning

confidence: 99%

“…The position of the needle was confirmed by a flow of clean cerebrospinal fluid. A solution of 100 μl was infused over 20 s and the needle was held in place for an additional 10 s before being withdrawn (Paronis et al, 1993;Shannon and Lutz, 2002).…”

Section: Methodsmentioning

confidence: 99%

Characterization of scratching responses in rats following centrally administered morphine or bombesin

Lee

Naughton

Woods

et al. 2003

Behavioural Pharmacology

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The aim of this study was to characterize scratching behavior elicited by central administration of morphine or bombesin in rats, and to determine the role of opioid receptors in scratching induced by both pruritogenic agents. Central administration included intracisternal (i.c.), intrathecal (i.t.), and intracerebroventricular (i.c.v.) routes. Scratching events made with hind paws were counted by observers blinded to treatment conditions. Intracisternal morphine (0.01-0.1 μg) produced dosedependent increases in scratching; the maximum response to i.c. morphine 0.1 μg was approximately 500 scratches within a 1-hour period. Neither i.t. nor i.c.v. morphine significantly increased scratching. Bombesin (0.01 -0.32 μg) elicited robust scratching following i.c. administration. The maximum response to i.c. bombesin 0.32 μg was approximately 4000 scratches within a 1-hour period. Both i.t. and i.c.v. bombesin produced profound scratching at similar doses. Antagonist studies confirmed that mu-opioid receptors selectively mediate i.c. morphine-induced scratching. However, selective mu-, kappa-, and delta-opioid antagonists did not attenuate i.c. bombesin-induced scratching. These results demonstrate that morphine and bombesin elicit scratching through different receptor mechanisms, at different central sites, and to different degrees.

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“…This effect seems to be manifested by activating peripheral -opioid receptors (Menendez et al 2003(Menendez et al , 2005Sevostianova et al 2005; Shannon and Lutz 2002); however, the existence of an additional mechanism is supported by several findings. First, loperamide-induced analgesia could be antagonized with naloxone only at doses 10-fold higher than those needed to antagonize morphine administered by the same route (Sevostianova et al 2005;Shannon and Lutz 2002); second, a significant antinociceptive effect of loperamide was found both ipsi-and contralateral to the thermal injury paw, with the effect at the contralateral site not being reversible with naloxone (Nozaki-Taguchi and Yaksh 1999); third, loperamide antagonized thermal hyperalgesia in morphine-tolerant rats, indicating a nonopioid mechanism of action (Nozaki-Taguchi and Yaksh 1999). Additionally, only high doses of loperamide were efficacious in reversal of the first phase of formalininduced acute pain (paw liking and biting), but failed to produce antinociceptive effects in a model of acute thermal pain (Sevostianova et al 2005).…”

Section: Physiological Significance Of Loperamide-induced I H Inhibitionmentioning

confidence: 99%

“…Local injection of loperamide and its analogs resulted in antipruritic activity in a mouse model of itch, and caused potent antinociception, inhibiting late phase formalin-induced flinching (DeHaven-Hudkins et al 2002). However, in the formalin test in rats, 10-fold higher doses of naloxone administered subcutaneously were needed to antagonize loperamide compared with the doses needed to antagonize morphine when the agonists were administered subcutaneously, suggesting that the effects of loperamide might be mediated in part by receptors different from those that mediate the effects of morphine (Shannon and Lutz 2002). In a thermal injury-induced rat model, loperamide was able to block thermal hyperalgesia in morphine-tolerant rats, indicating a nonopioid mechanism of action (Nozaki-Taguchi and Yaksh 1999).…”

Section: Introductionmentioning

confidence: 99%

Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

Vasilyev

Qin²,

Lu³

et al. 2007

Journal of Neurophysiology

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. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are responsible for the functional hyperpolarization-activated current (I h ) in dorsal root ganglion (DRG) neurons, playing an important role in pain processing. We found that the known analgesic loperamide inhibited I h channels in rat DRG neurons. Loperamide blocked I h in a concentration-dependent manner, with an IC 50 ϭ 4.9 Ϯ 0.6 and 11.0 Ϯ 0.5 M for large-and small-diameter neurons, respectively. Loperamideinduced I h inhibition was unrelated to the activation of opioid receptors and was reversible, voltage-dependent, use-independent, and was associated with a negative shift of V 1/2 for I h steady-state activation. Loperamide block of I h was voltage-dependent, gradually decreasing at more hyperpolarized membrane voltages from 89% at -60 mV to 4% at -120 mV in the presence of 3.7 M loperamide. The voltage sensitivity of block can be explained by a loperamide-induced shift in the steady-state activation of I h . Inclusion of 10 M loperamide into the recording pipette did not affect I h voltage for half-maximal activation, activation kinetics, and the peak current amplitude, whereas concurrent application of equimolar external loperamide produced a rapid, reversible I h inhibition. The observed loperamideinduced I h inhibition was not caused by the activation of peripheral opioid receptors because the broad-spectrum opioid receptor antagonist naloxone did not reverse I h inhibition. Therefore we suggest that loperamide inhibits I h by direct binding to the extracellular region of the channel. Because I h channels are involved in pain processing, loperamide-induced inhibition of I h channels could provide an additional molecular mechanism for its analgesic action.

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Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats

Cited by 109 publications

References 16 publications

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

Characterization of scratching responses in rats following centrally administered morphine or bombesin

Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

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Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats

Cited by 109 publications

References 16 publications

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

Characterization of scratching responses in rats following centrally administered morphine or bombesin

Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons

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Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons