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. 2004 Nov;63(Suppl 2):ii72–ii75. doi: 10.1136/ard.2004.029942

DREAMing about arthritic pain

H Cheng, J Penninger
PMCID: PMC1766765  PMID: 15479877

Abstract

The experience of acute pain serves a crucial biological purpose: it alerts a living organism to environmental dangers, inducing behavioural responses which protect the organism from further damage. In contrast, chronic pain arising from disease states and/or pathological functioning of the nervous system offers no advantage and may be debilitating to those afflicted. Despite recent advances in our understanding of pain mechanisms, the satisfactory management of pathological pain eludes current treatment strategies. We have demonstrated in a previous study on dream deficient mice the pivotal role of downstream regulatory element antagonistic modulator (DREAM) in modulating pain sensitivity in a number of behavioural models, including acute and chronic neuropathic pain. DREAM is a novel calcium binding transcriptional repressor for the prodynorphin gene in spinal cord neurones. The marked attenuation in pain behaviour exhibited by dream–/– mice was shown, by pharmacological and biochemical analyses, to be due to increased activation of the endogenous κ-opioid system. Importantly, loss of DREAM also attenuated inflammatory pain. Thus, DREAM and the DREAM pathway constitute a novel therapeutic paradigm for the treatment of chronic pain in arthritis.

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Figure 1.

Figure 1

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 A model for downstream regulatory element antagonistic modulator (DREAM) dependent modulation of pain transmission at the spinal level. Noxious stimulation of peripheral tissues activates peripheral sensory afferents and evokes the release of excitatory neurotransmitters from their central terminals onto the spinal dorsal horn. The nociceptive information is eventually relayed to higher pain processing centres within the brain, which, in turn, can provide descending modulation of nociceptive transmission at the spinal level. Generally speaking, spinal opioids such as dynorphin have inhibitory effects on nociceptive transmission. DREAM is expressed in the spinal cord and controls the expression of the prodynorphin gene. Loss of DREAM function—for example, by genetic deletion in our mouse model—results in elevated expression of prodynorphin and enhanced κ-opioid receptor activation under basal conditions. As a consequence, DREAM deficient mice exhibit a phenotype of "ongoing analgesia". DRG, dorsal root ganglion.

Selected References

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