Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis.

Background: This study examined the development of chronic pain, a cardinal symptom of rheumatoid arthritis (RA), in mice with antigen- and collagen-induced arthritis (ACIA). Since the role of CD8 T cells in arthritis is controversial, we investigated the consequences of CD8-depletion on arthritis development and opioid modulation of pain in this novel model of chronic autoimmune arthritis.

Methods: Disease severity in control and CD8-depleted animals was determined by histological assessment of knee-joint sections and measurement of autoantibody formation.

B Lymphocytes Express Pomc mRNA, Processing Enzymes and β-Endorphin in Painful Inflammation.

Immune cell-derived beta-endorphin (END) and other opioid peptides elicit potent and clinically relevant inhibition of pain (analgesia) in inflamed tissue by activation of peripheral opioid receptors. Pro-opiomelanocortin (POMC) is the polypeptide precursor of END and is processed by prohormone convertases (PCs). This study aims to decipher the processing of POMC in lymphocyte subsets in a rat model of unilateral painful hindpaw inflammation.

Leukocyte opioid receptors mediate analgesia via Ca(2+)-regulated release of opioid peptides.

Opioids are the most powerful analgesics. As pain is driven by sensory transmission and opioid receptors couple to inhibitory G proteins, according to the classical concept, opioids alleviate pain by activating receptors on neurons and blocking the release of excitatory mediators (e.g.

IL-4, JAK-STAT signaling, and pain.

During inflammation, several mediators directly or indirectly induce pain including pro-inflammatory cytokines and there is evidence that the JAK-STAT pathway is involved in the formation of pronociceptive cytokines. The same pathway, however, is also of importance for anti-inflammatory cytokines such as IL-4 to counteract the inflammatory reaction and-as it seems based on the current literature-nociceptive symptoms. Current therapeutic approaches targeting molecules of the JAK-STAT signaling cascade are auspicious but as this review demonstrates, more experimental and clinical studies are required to decipher the specific contribution of this pathway in the modulation of pain.

Functional characteristics of the naked mole rat μ-opioid receptor.

While humans and most animals respond to µ-opioid receptor (MOR) agonists with analgesia and decreased aggression, in the naked mole rat (NMR) opioids induce hyperalgesia and severe aggression. Single nucleotide polymorphisms in the human mu-opioid receptor gene (OPRM1) can underlie altered behavioral responses to opioids. Therefore, we hypothesized that the primary structure of the NMR MOR may differ from other species.

JAK-STAT1/3-induced expression of signal sequence-encoding proopiomelanocortin mRNA in lymphocytes reduces inflammatory pain in rats.

Background: Proopiomelanocortin (POMC)-derived beta-endorphin1-31 from immune cells can inhibit inflammatory pain. Here we investigated cytokine signaling pathways regulating POMC gene expression and beta-endorphin production in lymphocytes to augment such analgesic effects.

Results: Interleukin-4 dose-dependently elevated POMC mRNA expression in naïve lymph node-derived cells in vitro, as determined by real-time PCR.

Opioid receptors and opioid peptide-producing leukocytes in inflammatory pain--basic and therapeutic aspects.

This review summarizes recent findings on neuro-immune mechanisms underlying opioid-mediated inhibition of pain. The focus is on events occurring in peripheral injured tissues that lead to the sensitization and excitation of primary afferent neurons, and on the modulation of such mechanisms by immune cell-derived opioid peptides. Primary afferent neurons are of particular interest from a therapeutic perspective because they are the initial generators of impulses relaying nociceptive information towards the spinal cord and the brain.