Changes in the Effect of Spinal Prostaglandin E₂during Inflammation: Prostaglandin E (EP1-EP4) Receptors in Spinal Nociceptive Processing of Input from the Normal or Inflamed Knee Joint

Abstract

Inflammatory pain is caused by sensitization of peripheral and central nociceptive neurons. Prostaglandins substantially contribute to neuronal sensitization at both sites. Prostaglandin E 2 (PGE 2 ) applied to the spinal cord causes neuronal hyperexcitability similar to peripheral inflammation. Because PGE 2 can act through EP1-EP4 receptors, we addressed the role of these receptors in the spinal cord on the development of spinal hyperexcitability. Recordings were made from nociceptive dorsal horn neurons with main input from the knee joint, and responses of the neurons to noxious and innocuous stimulation of the knee, ankle, and paw were studied after spinal application of recently developed specific EP1-EP4 receptor agonists. Under normal conditions, spinal application of agonists at EP1, EP2, and EP4 receptors induced spinal hyperexcitability similar to PGE 2 . Interestingly, the effect of spinal EP receptor activation changed during joint inflammation. When the knee joint had been inflamed 7-11 hr before the recordings, only activation of the EP1 receptor caused additional facilitation, whereas spinal application of EP2 and EP4 receptor agonists had no effect. Additionally, an EP3␣ receptor agonist reduced responses to mechanical stimulation. The latter also attenuated spinal hyperexcitability induced by spinal PGE 2 . In isolated DRG neurons, the EP3␣ agonist reduced the facilitatory effect of PGE 2 on TTX-resistant sodium currents. Thus pronociceptive effects of spinal PGE 2 can be limited, particularly under inflammatory conditions, through activation of an inhibitory splice variant of the EP3 receptor. The latter might be an interesting target for controlling spinal hyperexcitability in inflammatory pain states.

Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain

“…Prostaglandin E 2 binds to 4 G protein-coupled receptors called EP 1 to EP 4 (encoded by Ptger1-4). We tested mice lacking EP 1 or EP 3 receptors, since these are strongly expressed in brain structures related to motivation (12,13) and have been shown to be implicated in nociceptive processing (14)(15)(16) Pain is fundamentally unpleasant and induces a negative affective state. The affective component of pain is mediated by circuits that are distinct from those mediating the sensory-discriminative component.…”

Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice

“…This model is particularly useful for studying central changes elicited by enhanced excitatory drive from the periphery into the spinal cord, because the primary hyperalgesia evoked in the injured knee is accompanied by secondary hyperalgesia in the ipsilateral and contralateral hind paws (ref. 27 and Figure 7A, left). As compared with control GluA1 fl/fl mice, SNS-GluA1 -/-mice also showed a significantly reduced drop in response thresholds to von Frey at the ipsilateral paw after knee injury (P < 0.05 at all time points except 4-5 days after induction of arthritis; Figure 7A) and a markedly reduced duration of chronic hypersensitivity ( Figure 7A).…”

Sensory and vascular changes in a rat monoarthritis model: prophylactic and therapeutic effects of meloxicam

“…In terms of possible factors underlying functional deficits, inflammatory joint disease is associated with a number of changes in the chemical balance in the joint and joint capsule [17][18][19], sensory neurons [20][21][22] and spinal cord [23][24][25], and with changes in nociceptive mechanisms of primary sensory neurons [26,27] and spinal cord neurons [25]. Prostaglandins are expressed in animal models of joint inflammation, in both the periphery [17] and spinal cord [23].…”