Immune cell–derived opioids protect against neuropathic pain in mice

Abstract

The analgesic effects of leukocyte-derived opioids have been exclusively demonstrated for somatic inflammatory pain, for example, the pain associated with surgery and arthritis. Neuropathic pain results from injury to nerves, is often resistant to current treatments, and can seriously impair a patient's quality of life. Although it has been recognized that neuronal damage can involve inflammation, it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, in this study we have demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy. About 30%-40% of immune cells that accumulated at injured nerves expressed opioid peptides such as β-endorphin, Met-enkephalin, and dynorphin A. Selective stimulation of these cells by local application of corticotropin-releasing factor led to opioid peptide-mediated activation of opioid receptors in damaged nerves. This ultimately abolished tactile allodynia, a highly debilitating heightened response to normally innocuous mechanical stimuli, which is symptomatic of neuropathy. Our findings suggest that selective targeting of opioid-containing immune cells promotes endogenous pain control and offers novel opportunities for management of painful neuropathies. IntroductionWithin inflamed tissues, a plethora of molecules such as protons, adenosine triphosphate, glutamate, neuropeptides (e.g., calcitonin gene-related peptide [CGRP], substance P), prostaglandins, bradykinin, cytokines, and chemokines can induce pain (1, 2). Concurrently, however, endogenous counterregulatory mechanisms are mounted. It has been established that somatic inflammatory (e.g., postoperative and arthritic) pain can be effectively controlled by the immune system, in both animals and humans (3,4). This is mediated by extravasating leukocytes, which produce and liberate opioid peptides in inflamed tissues. The released opioids bind to opioid receptors on peripheral sensory neurons, resulting in the inhibition of noxious impulse propagation (5-17). Such effects are particularly interesting because they occur directly in peripheral tissues and, therefore, are free of side effects such as nausea, depression of breathing, cognitive impairment, dependence, and addiction mediated by opioid receptors in the CNS (3).Neuropathic pain is a common consequence of nerve injuries caused by trauma such as amputation, entrapment, or compression. It is characterized by persistent burning or shooting sensations and heightened responses to normally noxious (hyperalgesia) and innocuous stimuli (allodynia). Despite increasing efforts, such pain remains poorly controlled, severely impacting patients ' well-being (18-20), which makes new therapeutic approaches highly desirable. Research over the last decade has provided evidence on the association of traumatic peripheral nerve injuries with inflammatory reactions mobilizing the immune system (1,

Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain

“…CRF applied at the CCI site in the most effective doses (20 ng at 2 days or 100 ng at 14 days) found earlier2930, significantly elevated von Frey thresholds, completely reversing mechanical hypersensitivity (to the thresholds before CCI) measured 30 min after injection, on days 2 and 14 following CCI in wild-type mice. In contrast, these CRF analgesic effects were virtually absent in END-KO, PENK-KO and PDYN-KO mice (Fig.…”

Roles of Gr-1+Leukocytes in Postincisional Nociceptive Sensitization and Inflammation

“…Also, the expression of opioid receptors on peripheral neurons is enhanced under inflammatory conditions 38,39 . Endogenous opioid peptides in sites of inflammation can be released spontaneously, though release is augmented by the presence of corticotropin-releasing factor or stress 40–42 . Importantly, in models of inflammation and metastatic bone cancer pain, the local injection of opioid receptor antagonists or antibodies enhance nociceptive sensitization by blocking local opioid signaling 15,42,43 .…”

“…Neutrophil depletion attenuated nerve injury induced hyperalgesia by potentially decreasing mediators responsible for induction of pain. However, local application of corticotropin-releasing factor to the site of nerve injury produced analgesia mediated by opioid containing leukocytes 40 . Therefore, it seems that the neutrophils and opioid peptides produced by them are participating in an intensely localized inflammatory response.…”

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

“…In patients undergoing arthroscopic knee surgery, opioid-containing immune cells are detectable in the inflamed synovium and the blockade of intra-articular opioid receptors by naloxone results in significantly increased postoperative pain for up to 4 h (Stein et al, 1993). More recently, peripheral opioid analgesia has also been reported in experimental neuropathic pain (Labuz et al, 2009, 2010). …”