ABSTRACT
Chronic inflammatory and neuropathic pain is often difficult to manage using conventional remedies. The underlying mechanisms and therapeutic strategies required for the management of chronic pain need to be urgently established. The cyclic AMP (cAMP) second messenger system has been implicated in the mechanism of nociception, and the inhibition of the cAMP pathway by blocking the activities of adenylyl cyclase (AC) and protein kinase A has been found to prevent chronic pain in animal models. However, little is known regarding which of the 10 known isoforms of AC are involved in nociceptive pathways. Therefore, we investigated the potential pronociceptive function of AC5 in nociception using recently developed AC5 knockout mice (AC5-/-). We found that AC5-/- mice show markedly attenuated pain-like responses in acute thermal and mechanical pain tests as compared with the wildtype control. Also, AC5-/- mice display hypoalgesic responses to inflammatory pain induced by subcutaneous formalin injection into hindpaws, and to non-inflammatory and inflammatory visceral pain induced by injecting magnesium sulfate or acetic acid into the abdomen. Moreover, AC5-/- mice show strongly suppressed mechanical and thermal allodynia in two nerve injury-induced neuropathic pain models. These results suggest that AC5 is essential for acute and chronic pain, and that AC5 knockout mice provide a useful model for the evaluation of the pathophysiological mechanisms of pain.
Subject(s)
Adenylyl Cyclases/metabolism , Isoenzymes/metabolism , Pain Threshold/physiology , Pain/enzymology , Signal Transduction/physiology , Adenylyl Cyclases/genetics , Animals , Isoenzymes/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Pain Measurement , Second Messenger Systems/physiologyABSTRACT
We examined whether the extent of sympathetic sprouting in the dorsal root ganglion was a function of the number of injured nerve fibers. We compared two groups of rats. One group was subjected to unilateral superior and inferior caudal trunk transections at the level between the S1 and S2 spinal nerves (S-I group) and the other group was subjected to unilateral superior caudal trunk transection at the same level (S group). Immunohistochemical staining with tyrosine hydroxylase (TH) antibody of the S1 DRG revealed that the degree of TH-immunoreactive fibers was more extensive in the S-I group than in the S group. However, there was no difference in the severity of neuropathic pain behaviors between the two groups. These results suggest that the extent of sympathetic sprouting in the DRG following peripheral nerve injury is proportionally related to the amount of injured nerve fibers, but not related to the degree of neuropathic pain behaviors.
Subject(s)
Adrenergic Fibers/physiology , Ganglia, Sensory/injuries , Ganglia, Sensory/physiology , Nerve Regeneration/physiology , Neurons/physiology , Animals , Ganglia, Spinal/metabolism , Male , Pain Measurement/methods , Peripheral Nerve Injuries , Peripheral Nerves/physiology , Rats , Rats, Sprague-DawleyABSTRACT
We tested the hypothesis that the decrease in spinal levels of SP and CGRP after peripheral nerve injury is related to neuropathic pain. We compared two groups of rats, both of which were subjected to unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves. One group exhibited well-developed neuropathic signs after the nerve injury, whereas the other group showed poorly developed signs despite the same nerve injury. The decrease in immunoreactivity of CGRP and SP in the S1 dorsal horn (injured segment) was not significantly different between the two groups. These results suggest that the decrease in spinal levels of CGRP and SP after peripheral nerve injury is not related to neuropathic pain.
Subject(s)
Calcitonin Gene-Related Peptide/metabolism , Pain/metabolism , Peptide Fragments/metabolism , Peripheral Nervous System Diseases/metabolism , Posterior Horn Cells/metabolism , Substance P/metabolism , Animals , Cold Temperature , Hot Temperature , Male , Physical Stimulation/methods , Rats , Rats, Sprague-Dawley , Spinal Nerves/injuriesABSTRACT
We examined whether signals from the neuroma or the dorsal root ganglion of the injured segment are critical for the generation of neuropathic pain. To this aim, we used a rat model of peripheral neuropathy made by transecting the inferior and superior caudal trunks at the level between the S1 and S2 spinal nerves under enflurane anesthesia. These animals displayed tail-withdrawal responses to normally innocuous mechanical stimulation applied to the tail with a von Frey hair (2 g). Also, these animals, compared to pre-surgical value, displayed shorter tail-withdrawal latencies following immersion of the tail to warm (40 degrees C) or cold (4 degrees C) water. Transection of the S1 spinal nerve between the dorsal root ganglion and neuroma did not change the behavioral signs of neuropathic pain. In contrast, S1 dorsal rhizotomy significantly reduced the behavioral signs. The data suggest that signals arising from the dorsal root ganglion cells of the injured segment, but not from the neuroma, are critical for the generation of neuropathic pain in this model.
