Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions

Abstract

Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors.

Clinical, behavioral and antinociceptive effects of crotalphine in horses

“…Nociceptive stimuli are conducted by different sensitive fibers to the dorsal horn of the spinal medulla and opioids modulate the nociceptive response and cause antinociceptive effect (TRUONG et al, 2003). As observed, crotalphine promoted more analgesia on inflamed tissue and this findingis supported by previous studies which revealed that expression and distribution of receptors in damaged tissue change the potency of opioids ( VAN LOON et al, 2013); there is also activation of peripheral opioid receptors depending on the stage of the inflammatory reaction and opioids do not always act the same way on intact tissue because they induce release of IL-10, which has anti-inflammatory effect (JOHNSTON et al, 2004;IWASZKIEWICZ, 2013) and increase plasmatic level of glucocorticoids by stimulation of the hypothalamicpituitary-adrenal axis (CHISARI et al, 1998). Besides, crotalphine was more efficient in the ischial region because mu receptors are distributed along the spinal medulla in horses, while kappa and delta receptors are restricted to the lumbosacral and cervical segments, respectively (VALADÃO et al, 2002).…”

Nicotine Effects and the Endogenous Opioid System

“…Peripheral tissue injury causes the migration of immune cells to the injured site (27). These cells express opioid peptides, such as b-endorphin, Met-Enk, and dynorphin A, together with corticotropin-releasing factor (CRF) receptor.…”

The immunomodulation of dynorphin 1-17 and its biotransformation fragments on inflammatory signalling pathways

“…The opioid receptors are also expressed on immune cells, suggesting that opioids have a direct effect on immune function in host defence and immunity (211). A substantial body of literature evidence over the past decades has shown that the immune-derived opioid peptides produce significant inhibition of inflammatory pain upon their interaction with opioid receptors expressed on the terminals of peripheral sensory neurons in inflamed tissue (10,11,78,142).…”

“…Several underlying mechanisms of opioidmediated peripheral analgesia have been shown including alteration in calcium influx, inhibition of calcitonin gene related peptide (CGRP) and cyclic adenosine monophosphate (cAMP) as well as activation of transient receptor potential vanilloid 1 (TRPV1) (13). Likewise, modification of inflammatory cascades has also been observed, thereby expanding the perspective that peripherally active endogenous opioids are not only restricted to analgesia but also possess on immunomodulatory component which is therapeutically beneficial in inflammation-induced pain (4,11). (34,35).…”

“…These spurred research into opioid pharmacological actions outside the CNS, leading to the discovery of peripheral opioid receptors, located on the peripheral sensory neurons (10). It has been reported previously that peripheral opioid receptor activation produced significantly potent and clinically measurable analgesia (11,12). Intriguingly, peripheral opioid action in treating pain is devoid of central side effects, thus underpinning this as a novel approach to treat pain (13).…”