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

Abstract

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.

Effects of Loperamide on Mechanical Allodynia Induced by Herpes Simplex Virus Type-1 in Mice

“…Loperamide is a potent agonist with nanomolar affinity for human µ-opioid receptors, but it also has relatively low affinity for δ-and κ-opioid receptors (3). Loperamide inhibits thermal hyperalgesia but not mechanical allodynia of mice given spinal nerve ligation, and the inhibition of thermal hyperalgesia is antagonized by a δ-opioid, but not µ-opioid, receptor antagonist (23). In addition, the inhibitory action of loperamide on the colonic mucosa has been claimed to be mediated by δ-and κ-opioid, but not µ-opioid, receptors (24).…”

IL-4, JAK-STAT signaling, and pain

“…Several drugs such as opioids, [1][2][3] nonsteroidal anti-inflammatory drugs (NSAIDs), 4,5 IL-1 receptor antagonist, 6 or antibodies, e.g., anti-nerve growth factor (NGF) 7 and anti-tumor necrosis factor (TNF)-α, 8 were studied in cancer pain models showing different efficacy. In neuropathic pain also opioids, [9][10][11] purinergic receptor antagonist, 12 and enkephalindegrading inhibitors 13 have been tested. Although inflammatory pain has its own etiology, both cancer and neuropathic pain share an inflammatory component, which makes inflammatory pain the broadest type of pain.…”

Electromagnetic millimeter wave induced hypoalgesia: Frequency dependence and involvement of endogenous opioids

“…The general logic of the present experiments is as follows: if the selective pharmacological blockage of a certain type of OR is followed by the disappearance (or significant reduction) of the MWT-induced hypoalgesia in the cTFT, then this particular type of OR is involved in the development of the effect [Shinoda et al, 2007]. The following selective blockers of OR were used: (1) m 1 /m 2 -OR antagonist b-funaltrexamine (b-FNA).…”