preproenkephalin and Hyperesthesia

Nerve injury-induced afferent discharge is thought to elicit spinal sensitization and consequent abnormal pain. Experimental neuropathic pain, however, also depends on central changes, including descending facilitation arising from the rostral ventromedial medulla (RVM) and upregulation of spinal dynorphin. A possible intersection of these influences at the spinal level was explored by measuring evoked, excitatory transmitter release in tissues taken from nerve-injured animals with or without previous manipulation of descending modulatory systems. Spinal nerve ligation (SNL) produced expected tactile and thermal hyperesthesias. Capsaicin-evoked calcitonin gene-related peptide (CGRP) release was markedly enhanced in lumbar spinal tissue from SNL rats when compared with sham-operated controls. Enhanced, evoked CGRP release from SNL rats was blocked by anti-dynorphin A(1-13) antiserum; this treatment did not alter evoked release in tissues from sham-operated rats. Dorsolateral funiculus lesion (DLF) or destruction of RVM neurons expressing mu-opioid receptors with dermorphin-saporin, blocked tactile and thermal hypersensitivity, as well as SNL-induced upregulation of spinal dynorphin. Spinal tissues from these DLF-lesioned or dermorphin-saporin-treated SNL rats did not exhibit enhanced capsaicin-evoked CGRP-IR release. These data demonstrate exaggerated release of excitatory transmitter from primary afferents after injury to peripheral nerves, supporting the likely importance of increased afferent input as a driving force of neuropathic pain. The data also show that modulatory influences of descending facilitation are required for enhanced evoked transmitter release after nerve injury. Thus, convergence of descending modulation, spinal plasticity, and afferent drive in the nerve-injured state reveals a mechanism by which some aspects of nerve injury-induced hyperesthesias may occur.

Topics: Afferent Pathways; Analgesics, Opioid; Animals; Calcitonin Gene-Related Peptide; Capsaicin; Disease Models, Animal; Dynorphins; Enkephalins; Hyperesthesia; Ligation; Lumbosacral Region; Male; Medulla Oblongata; Microinjections; N-Glycosyl Hydrolases; Nerve Compression Syndromes; Neuralgia; Neuronal Plasticity; Neurotransmitter Agents; Oligopeptides; Opioid Peptides; Pain Measurement; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Recombinant Fusion Proteins; Ribosome Inactivating Proteins, Type 1; Saporins; Sensory Thresholds; Spinal Cord; Spinal Nerves

A unilateral experimental inflammation of the hindlimb produces hyperalgesia to both mechanical and radiant thermal stimuli that is rapid in onset. During this period, parameters of dynorphin biosynthesis are elevated to a much greater degree than those of the enkephalin system. An increase in the content of the peptide dynorphin A(1-8) occurs in the spinal cord segments that receive sensory input from the affected limb. This is accompanied by a rapid (within 24 h) and pronounced increase in the levels of mRNA coding for the dynorphin protein precursor. Maximum elevations (6- to 8-fold) of preprodynorphin mRNA are observed between days 2 and 5 subsequent to the induction of inflammation. Compared to the increase in mRNA, the increase in dynorphin A(1-8) peptide was appreciably delayed and proportionately less; maximal increases in peptide (3-fold) were seen at day 5 of inflammation. Dorsal spinal cord preproenkephalin mRNA is elevated to a lesser degree (50-80%). However, the increase in preproenkephalin mRNA is apparently not enough to yield a measurable increase in the proenkephalin-derived peptide met5-enkephalin-Arg6-Gly7-Leu8, the levels of which showed no significant change during the 14-day inflammatory period. These data suggest the active participation of opioid neurons, especially those containing dynorphin, at the spinal level, in the modulation of sensory afferent input during peripheral inflammatory pain states.

Topics: Animals; DNA; Dynorphins; Enkephalin, Methionine; Enkephalins; Hyperalgesia; Hyperesthesia; Male; Nucleic Acid Hybridization; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred Strains; RNA, Messenger