Cyclooxygenase‐2 is induced in the endothelial cells throughout the central nervous system during carrageenan‐induced hind paw inflammation; its possible role in hyperalgesia

Abstract

Inflammation is often accompanied with hyperalgesia. This hyperalgesia is mediated partly by prostaglandin(s) produced in the CNS through the cyclooxygenase-2 (COX-2) dependent pathway. However, it remains unclear where COX-2 is induced in the CNS during inflammation, and how it is involved in hyperalgesia. We studied the precise site of COX-2 induction in the CNS, the relation between the time course of COX-2 induction and that of hyperalgesia, and the effect of COX-2-selective inhibitor by using a carrageenan model. Carrageenan injection induced expression of COX-2-like immunoreactivity in vascular endothelial cells throughout the CNS. This response became evident by 3 h, and was most prominent at 6 h after carrageenan injection. This COX-2 induction was associated with an elevation of prostaglandin E 2 in the cerebrospinal fluid, being evident at 3 h, larger at 6 h, and alleviated by a COX-2-selective inhibitor. Thermal hyperalgesia became evident at 1 h, further increased thereafter, and remained elevated until 6 h. Intrathecal administration of COX-2-selective inhibitor 2 h after the carrageenan injection exerted a prominent therapeutic effect on hyperalgesia. These results demonstrate that, during carrageenan-induced inflammation, endothelial cells are the major source of prostaglandin(s) in the CNS, and this endothelial expression of COX-2 is involved in the inflammation-induced hyperalgesia.

Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain

“…Carrageenan induces a short-term inflammation involving prostanoids (27). Nerve growth factor (NGF) acting through TrkA receptors also causes hyperalgesia (28).…”

Pain Attenuation With Low Level Laser Therapy on Periarthritis Scapulohumeralis

“…Neuropeptides (7) such as glutamic acid, substance P and calcitonin gene related peptides which are all produced at the dorsal root ganglion have been reported as being closely associated with cyclooxygenase 2 (COX2) activation, (20,21) through which in turn subsequent PGE2 (6)(7)(8) generation and EP3 (22) subtype expression in the spinal cord (4,5) are implicated in the maintenance of the pain state (8) as well as in the occurrence of hyperalgesia (23) and allodynia. (24) Neuropathic pain is usually resistant to analgesics and can be very difficult to treat.…”

“…Out of the pro-inflammatory prostanoids (3) , prostaglandin (PG)E2 plays an important role in the delineation of the nociception in the peripheral nervous system (3) as well as in the spinal cord (4,5) .…”

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

“…While largely neglected at that time this study gained more attention when the antipyretic effect of local anesthetics blocking C-fiber-signaling was verified by Roth's group (Ross et al, 2000;Roth and De Souza, 2001). Several models for local inflammation have been used, including subcutaneous turpentine (Cooper and Rothwell, 1991;Fantuzzi et al, 1997;Horai et al, 1998;Kozak et al, 1998;Laflamme and Rivest, 1999;Leon et al, 1996), carrageenaninduced paw edema (Guay et al, 2004;Ibuki et al, 2003;Oka et al, 2007;Posadas et al, 2004;Prajapati et al, 2014), or immune stimuli administrated in artificial subcutaneous chambers (Cartmell et al, 2000;Miller et al, 1997;Rummel et al, 2005;Rummel et al, 2011;Zhang et al, 2008). However, most studies used local inflammation-models primarily to demonstrate an endotoxin-free cytokine-induced sickness syndrome (Horai et al, 1998;Kozak et al, 1998;Leon et al, 1996;Miller et al, 1997;Rivest et al, 2000) and not to investigate the role played by the afferent neurons.…”

“…However, most studies used local inflammation-models primarily to demonstrate an endotoxin-free cytokine-induced sickness syndrome (Horai et al, 1998;Kozak et al, 1998;Leon et al, 1996;Miller et al, 1997;Rivest et al, 2000) and not to investigate the role played by the afferent neurons. Thus, a humoral component was present in these models for local inflammation with measurable circulating cytokines (Horai et al, 1998;Kozak et al, 1998;Miller et al, 1997;Oka et al, 2007;Rummel et al, 2011) and brain expression of IkBα (Laflamme and Rivest, 1999), COX-2 (Horai et al, 1998;Ibuki et al, 2003;Oka et al, 2007), and PGE2 (Guay et al, 2004;Ibuki et al, 2003;Oka et al, 2007).…”