Neuropharmacology
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The 5-HT(4) receptor agonist tegaserod (TEG) has been reported to modulate visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the analgesic mechanism and site of action of TEG. ⋯ While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by GR113808, NLX and β-funaltrexamine (β-FNA) when injected into the RVM. Results indicate that TEG produces analgesia via activation of supraspinal 5-HT(4) receptors which triggers the release of opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce analgesia.
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Comparative Study
AS1069562, the (+)-isomer of indeloxazine, but not duloxetine has a curative-like analgesic effect in a rat model of streptozotocin-induced diabetic neuropathy.
AS1069562 is the (+)-isomer of indeloxazine, which had been clinically used as a cerebral activator for the treatment of cerebrovascular diseases with serotonin and norepinephrine reuptake inhibition (SNRI) and neuroprotection. Here, we compared the analgesic effects of repeated treatment with AS1069562 and duloxetine, a selective SNRI, on pain-related behavior in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Further, we also evaluated the effects on the expression of neurotrophic factors and nerve conduction velocity. ⋯ The results of this study indicate that the analgesic effect of repeated dosing of AS1069562 but not duloxetine is persistent even after a 1-week drug discontinuation in STZ-induced diabetic rats. Restoration of neurotrophic factors may be involved in the curative-like pharmacological effect of this agent. Thus, AS1069562 may potentially offer a better treatment option for patients with painful diabetic neuropathy than duloxetine via different mechanisms.
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Angiotensin (Ang) II exaggerates cerebral injury in ischemic damage. Angiotensin-converting enzyme type 2 (ACE2) converts Ang II into Ang (1-7) and thus, may protect against the effects of Ang II. We hypothesized that neuronal ACE2 over-expression decreases ischemic stroke in mice with Ang II overproduction. ⋯ Two days after surgery, brain samples were collected for various analyses. Results showed: 1) When compared to chronically hypertensive RA mice, SARA mice had lower basal MAP, less MCAO-induced infarct volume, and increased CBF, neurological function and cerebral microvascular density in the peri-infarct area; 2) These changes in SARA mice were not altered after MAP "clamping", but partially reversed by brain infusion of A-779; 3) Ang (1-7)/Ang II ratio, angiogenic factors, endothelial nitric oxide synthase (eNOS) expression and nitric oxide production were increased, whereas, NADPH oxidase subunits and reactive oxygen species were decreased in the brain of SARA mice. ACE2 protects brain from ischemic injury via the regulation of NADPH oxidase/eNOS pathways by changing Ang (1-7)/Ang II ratio, independently of MAP changes.
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Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves responds differently to alleviating drugs at cephalic versus extracephalic level. Because neuropathic pain evoked by anti-cancer drugs differs from that triggered by mechanical nerve lesion, we investigated whether differences between cephalic and extracephalic levels could also be characterized in rodents rendered neuropathic by treatment with the anti-cancer platinum derivative oxaliplatin. C57BL/6J mice received two injections and Sprague-Dawley rats three injections of oxaliplatin (10 mg/kg, i.p.) or its vehicle, with three days intervals. ⋯ Among the various markers investigated, only TRPA1 transcript was upregulated in ganglia of oxaliplatin-treated rats. These data showed that oxaliplatin induced supersensitivity to various stimuli in both cephalic and extra-cephalic territories in rodents. Regional differences in the efficacy of drugs to alleviate oxaliplatin-induced allodynia/hyperalgesia further support the idea that mechanisms underlying neuropathic pain have peculiarities at cephalic versus extra-cephalic level.
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Although previous reports have suggested that P2Y1 receptors (P2Y1Rs) are involved in cutaneous nociceptive signaling, it remains unclear how P2Y1Rs contribute to peripheral sensitization. The current study was designed to delineate the role of peripheral P2Y1Rs in pain and to investigate potential linkages to mitogen-activated protein kinase (MAPK) in DRGs and Transient Receptor Potential Vanilloid 1 (TRPV1) expression in a rodent inflammatory pain model. Following injection of 2% carrageenan into the hind paw, expressions of P2Y1 and TRPV1 and the phosphorylation rates of both p38 MAPK and ERK but not JNK were increased and peaked at day 2 post-injection. ⋯ Furthermore, inhibition of p38 activation in the DRGs by SB203580 (a p38 inhibitor, i.t, D0 to D2) prevented the upregulation of TRPV1 and a single i.t injection of SB203580 reversed the established thermal hyperalgesia, but not mechanical allodynia. Lastly, to identify the mechanism of action of P2Y1Rs, we repeatedly injected the P2Y1 agonist, MRS2365 into the naïve rat's hind paw and observed a dose-dependent increase in TRPV1 expression and p38 MAPK phosphorylation. These data demonstrate a sequential role for P2Y1R, p38 MAPK and TRPV1 in inflammation-induced thermal hyperalgesia; thus, peripheral P2Y1Rs activation modulates p38 MAPK signaling and TRPV1 expression, which ultimately leads to the induction of thermal hyperalgesia.