Trichinella spiralis
infection causes hyperexcitability in enteric after-hyperpolarising (AH) sensory neurons that is mimicked by neural, immune or inflammatory mediators known to stimulate
adenylyl cyclase (AC)/cyclic 3',5'-adenosine monophosphate (cAMP) signaling. The hypothesis was tested that ongoing modulation and sustained amplification in the AC/cAMP/phosphorylated cAMP related
element binding protrein (pCREB) signaling pathway contributes to hyperexcitability and neuronal plasticity in gut sensory neurons after
nematode infection. Electrophysiological, immunological, molecular
biological or immunochemical studies were done in T. spiralis-infected guinea-pigs (8000 larvae or saline) after acute-
inflammation (7 days) or 35 days p.i., after intestinal clearance. Acute-
inflammation caused AH-cell hyperexcitability and elevated mucosal and neural tissue levels of
myeloperoxidase,
mast cell tryptase,
prostaglandin E2, leukotrine B4, lipid peroxidation,
nitric oxide and
gelatinase; lower level
inflammation persisted 35 days p.i. Acute exposure to blockers of AC,
histamine,
cyclooxygenase or
leukotriene pathways suppressed AH-cell hyperexcitability in a reversible manner. Basal cAMP responses or those evoked by
forskolin (FSK), Ro-20-1724,
histamine or
substance P in isolated myenteric ganglia were augmented after T. spiralis
infection; up-regulation also occurred in AC expression and AC-immunoreactivity in
calbindin (AH) neurons. The cAMP-dependent slow excitatory synaptic transmission-like responses to
histamine (mast cell mediator) or
substance P (
neurotransmitter) acting via
G-protein coupled receptors (GPCR) in AH neurons were augmented by up to 2.5-fold after T. spiralis
infection. FSK,
histamine,
substance P or T. spiralis acute
infection caused a 5- to 30-fold increase in cAMP-dependent nuclear CREB phosphorylation in isolated ganglia or
calbindin (AH) neurons. AC and CREB phosphorylation remained elevated 35 days p.i.. Ongoing immune activation, AC up-regulation, enhanced
phosphodiesterase IV activity and facilitation of the GPCR-AC/cAMP/pCREB signaling pathway contributes to T. spiralis-induced neuronal plasticity and AH-cell hyperexcitability. This may be relevant in gut
nematode infections and
inflammatory bowel diseases, and is a potential therapeutic target.