Freezing of Enkephalinergic Functions by Multiple Noxious Foci: A Source of Pain Sensitization?

Abstract

BackgroundThe functional significance of proenkephalin systems in processing pain remains an open question and indeed is puzzling. For example, a noxious mechanical stimulus does not alter the release of Met-enkephalin-like material (MELM) from segments of the spinal cord related to the stimulated area of the body, but does increase its release from other segments.Methodology/Principal FindingsHere we show that, in the rat, a noxious mechanical stimulus applied to either the right or the left hind paw elicits a marked increase of MELM release during perifusion of either the whole spinal cord or the cervico-trigeminal area. However, these stimulatory effects were not additive and indeed, disappeared completely when the right and left paws were stimulated simultaneously.Conclusion/SignificanceWe have concluded that in addition to the concept of a diffuse control of the transmission of nociceptive signals through the dorsal horn, there is a diffuse control of the modulation of this transmission. The “freezing” of Met-enkephalinergic functions represents a potential source of central sensitization in the spinal cord, notably in clinical situations involving multiple painful foci, e.g. cancer with metastases, poly-traumatism or rheumatoid arthritis.

Synaptic upregulation and superadditive interaction of dopamine D2- and μ-opioid receptors after peripheral nerve injury

“…Although the molecular basis for this change is unclear, opioidergic modulation of dopamine efflux in the dorsal horn can be considered as a potential mechanism. Consistent with this view is the fact that opioids can influence dopamine release in the CNS [71][72][73] and promote the release of endogenous MOR ligands (such as met-enkephalin) that are present in superficial laminae of the dorsal horn [50] and are known to be promoted by noxious stimulation [16,42]. This suggests that an important determinant of D2R-mediated modulation may be endogenous MOR activity, which becomes tonically active after SNL while showing negligible activity basally [15].…”