A Review of the Effects of Pain and Analgesia on Immune System Function and Inflammation: Relevance for Preclinical Studies

Abstract

One of the most significant challenges facing investigators, laboratory animal veterinarians, and IACUCs, is how to balance appropriate analgesic use, animal welfare, and analgesic impact on experimental results. This is particularly true for in vivo studies on immune system function and inflammatory disease. Often times the effects of analgesic drugs on a particular immune function or model are incomplete or don't exist. Further complicating the picture is evidence of the very tight integration and bidirectional functionality between the immune system and branches of the nervous system involved in nociception and pain. These relationships have advanced the concept of understanding pain as a protective neuroimmune function and recognizing pathologic pain as a neuroimmune disease. This review strives to summarize extant literature on the effects of pain and analgesia on immune system function and inflammation in the context of preclinical in vivo studies. The authors hope this work will help to guide selection of analgesics for preclinical studies of inflammatory disease and immune system function.

Figures

Figure 1.

Interactions between nociceptive neurons and microglial cells after neuronal damage or activation by alarmins are depicted. l-glutamate (l-glu), substance P (SubP), adenosine triphosphate (ATP), brain-derived neurotrophic factor (BDNF), cysteine-cysteine chemokine ligand CCL2 neurokinin-1 receptors (NK-1R), extracellular signal-regulated kinase (ERK), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR), cyclic adenosine monophosphate response element binding protein (CREB). ATP purinergic receptors, (P2X7, P2Y12 and P2Y13R), mitogen-activated kinase (p38), c-jun-N terminal kinase (JNK), nuclear factor kappa B (NFκB), Interleukin-1β (IL1β) and its receptor, (IL-1R) tumor necrosis factor α (TNFα) and its receptor (TNFR), chloride (Cl−) transporter (KCC2), gamma aminobutyric acid A receptor (GABAA), chemokine ligand 2 (CCL2), chemokine receptor 2,3 (CCR2, CCR3), Cathepsin S (CatS), fractalkine (FKN, also termed CX3C-chemokine ligand 1), chemokine receptor 1 (CX3CR), Matrix metalloprotease 2, 9 (MMP2 MMP9), toll-like receptor 4 (TLR4).Reprinted by permission from Wolters Kluwer Health. Central neuron-glia interactions and neuropathic pain, Eduardo E. Benarroch 2010

Figure 2.

Summary of vaccine and antibody production models in which analgesic effects were evaluated. HI – humeral immunity, CMI – cell mediated immunity, SID – once a day, BID – twice a day, PO – by mouth, SC – subcutaneous, IP - intraperitoneal

Figure 3.

Summary of inflammation models in which analgesic effects were evaluated. IT – intrathecal, SID – once a day, BID – twice a day, PO – by mouth, SC – subcutaneous, IP - intraperitoneal

Figure 4.

Summary of IBD models in which analgesic effects were evaluated. SID – once a day, BID – twice a day, PO – by mouth, SC – subcutaneous, IP - intraperitoneal