a-889425 and Disease-Models--Animal

Visceral afferents expressing transient receptor potential (TRP) channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. Using a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice weekly) of caerulein-induced AP (AP), we studied the involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis and sprouting of pancreatic nerve fibers, and increased TRPV1 and TRPA1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated before week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked the development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1, and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked the development of CP and pain behaviors even when mice were challenged with seven more weeks of twice weekly caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest: (1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, (2) that there is a transition from AP to CP, after which TRP channel antagonism is ineffective, and thus (3) that early intervention with TRP channel antagonists may attenuate the transition to and development of CP effectively.

Topics: Amidines; Analgesics, Opioid; Analysis of Variance; Animals; Antigens, Differentiation; Calcitonin Gene-Related Peptide; Calcium; Ceruletide; Disease Models, Animal; Disease Progression; Exploratory Behavior; Extracellular Signal-Regulated MAP Kinases; Ganglia, Spinal; Gene Expression Regulation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Monocytes; Morphine; Neutrophil Infiltration; Nodose Ganglion; Oximes; Pain; Pain Measurement; Pancreas; Pancreatitis, Chronic; Peroxidase; Pyridines; RNA, Messenger; Sensory Receptor Cells; Time Factors; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

The TRPV1 receptor functions as a molecular integrator, and blockade of this receptor modulates enhanced somatosensitivity across several animal models of pathological pain, including models of osteoarthritic (OA) pain. In order to further characterize the contributions of TRPV1 to OA-related pain, we investigated the systemic effects of a selective TRPV1 receptor antagonist, A-889425, on grip force behavior, and on the evoked and spontaneous firing of spinal wide dynamic range (WDR) and nociceptive specific (NS) neurons in the monoiodoacetate (MIA) model of OA. Administration of A-889425 (10-300 μmol/kg, p.o.) alleviated grip force impairment in OA rats 3 weeks after the MIA injection. Also at 3 weeks post-MIA injection, the responses of WDR and NS neurons to 300 g von Frey hair stimulation of the knee joint were significantly reduced by A-889425 administration (10 and 30 μmol/kg, i.v.) in OA, but not sham-OA rats. Spontaneous firing of WDR neurons was elevated in the OA rats compared to sham-OA rats and may reflect ongoing discomfort in the OA animal. In addition to an effect on mechanotransmission, systemic administration of A-889425 reduced the elevated spontaneous firing of WDR neurons in OA rats but did not alter spontaneous firing in sham rats. The present data demonstrate that blockade of TRPV1 receptors modulates the firing of two important classes of spinal nociceptive neurons in a rat model of OA. The effect of A-889425 on neuronal responses to intense mechanical stimulation of the knee and on the spontaneous firing of WDR neurons adds to the growing appreciation for the role of TRPV1 receptors in pathological mechanotransmission and possibly non-evoked discomfort, respectively.

Topics: Animals; Disease Models, Animal; Electrophysiology; Male; Nociceptors; Osteoarthritis; Pain; Pyridines; Rats; Rats, Sprague-Dawley; Spinal Cord; TRPV Cation Channels

TRPV1 receptors are activated and/or modulated by noxious heat, capsaicin, protons and other endogenous agents released following tissue injury. There is a growing appreciation that this molecular integrator may also have a role in mechanosensation. To further understand this role, we investigated the systemic and site-specific effects of a selective TRPV1 receptor antagonist, A-889425, on low-intensity mechanical stimulation in inflamed rats. Systemic administration of A-889425 (30 and 100 micromol/kg po) reduced mechanical allodynia in complete Freund's adjuvant (CFA)-inflamed rats. Systemic A-889425 (3 and 10 micromol/kg iv) also decreased the responses of spinal wide dynamic range (WDR) neurons to low-intensity mechanical stimulation in CFA-inflamed but not uninjured rats. This effect of A-889425 was likely mediated via multiple sites since local injection of A-889425 into the spinal cord (1-3 nmol), ipsilateral hindpaw (200 nmol), and cerebral ventricles (30-300 nmol) all attenuated WDR responses to low-intensity mechanical stimulation. In addition to an effect on mechanotransmission, systemic administration of A-889425 reduced the spontaneous firing of WDR neurons in inflamed but not uninjured rats. Spontaneous firing is elevated after injury and may reflect ongoing pain in the animal. Local injection experiments indicated that this effect of A-889425 on spontaneous firing was mainly mediated via TRPV1 receptors in the spinal cord. Thus the current data demonstrate that TRPV1 receptors have an enhanced role after an inflammatory injury, impacting both low-intensity mechanotransmission and possibly spontaneous pain. Furthermore this study delineates the differential contribution of central and peripheral TRPV1 receptors to affect spontaneous or mechanically evoked firing of WDR neurons.

Topics: Action Potentials; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Evoked Potentials, Somatosensory; Freund's Adjuvant; Inflammation; Male; Neurons; Pain Threshold; Physical Stimulation; Pyridines; Rats; Rats, Sprague-Dawley; Spinal Cord; TRPV Cation Channels