Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats

Abstract

Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5 mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0 mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 µg/50 µL intraplantarly) and D-Ala2-MePhe4-Glyol5 enkephalin (300 µg/50 µL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5 mg/kg intraperitoneally) and MK-801 (0.2 mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3 mg/kg subcutaneously), but not loperamide (3 mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca2+]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 µM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide’s inhibition of KCl-elicited [Ca2+]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug administration.

Temporal changes in MrgC expression after spinal nerve injury

“…Therefore, we used the modified “Chung” model (L5 SNL), in which the nerve injury is standardized and limited to L5 (Guan et al, 2010b; He et al, 2013), to investigate the respective effects of SNL on injured and adjacent uninjured DRGs at various post-injury time points. We chose rats for this set of experiments because L5 SNL is easier to perform in rats than in mice, and more DRG tissue can be harvested from rats.…”

Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia

“…MOR at the peripheral nerve terminals in the skin, along the nociceptor axons, or at the nociceptor cell body). Note, however, that repeated intradermal administration of MOR agonists 23 , which arguably only act on MOR at nociceptor peripheral terminals, or chronic administration of the peripherally acting opioid loperamide 48 is sufficient to induce OIH and/or antinociceptive tolerance.…”

Activation of Peripheral μ-opioid Receptors by Dermorphin [d-Arg2, Lys4] (1–4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain

“…Our recent study suggested that repeated use of loperamide for alleviating neuropathic mechanical hypersensitivity may lead to the development of tolerance, possibly at peripheral opioid receptors. 51 Because different MOR agonists induce different magnitudes of receptor internalization, desensitization, and tolerance processes, it remains to be tested whether DALDA leads to the development of analgesic tolerance or opioid-induced hyperalgesia.…”