Rapid communicationMacromolecular synthesis contributes to nociceptive response to subcutaneous formalin injection in mice
Introduction
The formalin test is a widely used animal model for studying persistent pain (Dubuisson and Dennis, 1977). Formalin injected subcutaneously into the hindpaw produces a biphasic neuronal or behavioral response: a first phase (phase 1, 0–10 min) followed by another prolonged phase (phase 2, 10–55 min) (Dubuisson and Dennis, 1977). Pharmacological studies suggest that activation of NMDA receptors during phase 1 is critical for the induction of phase 2 (see Coderre et al., 1993for a review).
NMDA receptor-dependent synaptic plasticity is well investigated in the central nervous system, in particular, long-term potentiation (LTP) in the hippocampus (see Bliss and Collingridge, 1993for a review). New RNA and protein synthesis are critical for late-phase LTP (Frey et al., 1988, Frey et al., 1993, Nguyen et al., 1994). Peripheral noxious stimuli, including formalin injection, activate various immediate early genes in the spinal cord (Hunt et al., 1987, Wisden et al., 1990; see Coderre et al., 1993for a review), and tetanic stimulation of primary afferent fibers induces LTP in the dorsal horn of the spinal cord (Randic et al., 1993, Pockett, 1995, Liu and Sandkühler, 1997). We demonstrate here that new RNA and protein synthesis can contribute to behavioral nociceptive responses to formalin injection.
Section snippets
Formalin test
Adult, male mice were used (C57BL/6j; weight, 16–24.4 g; Jackson). The room temperature was maintained at 20°C. The animal protocol was approved by the Animal Studies Committee in Washington University. Formalin (5%, 10 μl) was injected into the dorsal skin of one side of the hindpaw. Licking the injected hindpaw was recorded as a nociceptive response. The total time of the responses was measured every 5 min. Phase 1 was the total response between the start of the injection and 10 min after the
Results
First, we wanted to test if inhibitors of new protein synthesis affect the behavioral response to acute noxious stimuli. Actinomycin D injected intraperitoneally (i.p.; 0.1, 1 or 10 mg/kg) did not significantly affect the spinal nociceptive TF reflex (mean baseline latency, 5.2±0.4 s; F(3,36)=1.53). The HP response, which requires licking the hindpaw, was also not affected by i.p. actinomycin D (mean baseline latency, 12.3±1.5 s; F(3,36)=0.33). These findings show that actinomycin D does not
Discussion
In the present study, we present pharmacological evidence that new RNA and protein synthesis contributes partially to phase 2 responses induced by formalin injection. Neither baseline nociceptive thresholds nor phase 1 were affected by the same treatment. The effects of actinomycin D/anisomycin are dose-related, and unlikely to be due to non-selective side effects (see also Linden, 1996). Our results suggest that plastic changes in the spinal cord, including new RNA and protein synthesis, could
Acknowledgements
This work was supported by a grant from the NIDA (DA10833).
References (13)
- et al.
Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence
Pain
(1993) - et al.
The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats
Pain
(1977) - et al.
Anisomycin, an inhibitor of protein synthesis, blocks late-phase of LTP phenomena in the hippocampal CA1 region in vitro
Brain Res.
(1988) - et al.
Intrathecal morphine in mice: a new technique
Eur. J. Pharmacol.
(1980) A protein synthesis-dependent late phase of cerebellar long-term depression
Neuron
(1996)Long-term potentiation and depression in the intermediate gray matter of rat spinal cord in vitro
Neuroscience
(1995)
Cited by (21)
Translational Control Mechanisms in Persistent Pain
2018, Trends in NeurosciencesTranslational Control of Chronic Pain
2015, Progress in Molecular Biology and Translational ScienceCitation Excerpt :The early-phase response (0–10 min) is caused predominantly by the peripheral C-fiber activation, whereas the late-phase response (10–55 min) is believed to be caused largely by functional changes in the dorsal horn of the spinal cord. Inhibition of general protein synthesis in the spinal cord using intrathecal administration of anisomycin, dramatically reduces pain behavior in the second phase of the formalin test, whereas the first phase is not affected.103 Moreover, mTOR inhibition using intrathecal delivery of rapamycin reduces nociceptive behavior during the second phase of formalin test88,104,105 and attenuates formalin-induced neuronal hyperexcitability in the wide dynamic range dorsal horn spinal neurons.104
Mitochondrial connection in chronic pain
2010, PainCentral plasticity and persistent pain
2004, Drug Discovery Today: Disease Models