Pain
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Human experimental pain models are widely used to study drug effects under controlled conditions. However, efforts to improve both animal and human experimental model selection, on the basis of increased understanding of the underlying pathophysiological pain mechanisms, have been disappointing, with poor translation of results to clinical analgesia. We have developed an alternative approach to the selection of suitable pain models that can correctly predict drug efficacy in particular clinical settings. ⋯ Significance limits were derived by random permutations of agreements. We found that a limited subset of pain models predicts a large number of clinically relevant pain settings, including efficacy against neuropathic pain for which novel analgesics are particularly needed. Thus, based on empirical evidence of agreement between drugs for their efficacy in experimental and clinical pain settings, it is possible to identify pain models that reliably predict clinical analgesic drug efficacy in cost-effective experimental settings.
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The ability to sense and respond to thermal stimuli at varied environmental temperatures is essential for survival in seasonal areas. In this study, we show that mice respond similarly to ramping changes in temperature from a wide range of baseline temperatures. ⋯ The adjustment of this set point requires transient receptor potential cation channel, subfamily member 8 (TRPM8), but not transient receptor potential cation channel, subfamily A, member 1 (TRPA1), and is regulated by phospholipase C (PLC) activity. Overall, our findings suggest that temperature response thresholds in mice are dynamic, and that this ability to adapt to environmental temperature seems to mirror the in vitro findings that PLC-mediated hydrolysis of phosphoinositol 4,5-bisphosphate modulates TRPM8 activity and thereby regulates the response thresholds to cold stimuli.
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Comparative Study
The Anti-Hyperalgesic Effects of a Novel TRPM8 Agonist in Neuropathic Rats: A Comparison with Topical Menthol.
Menthol has historically been used topically to alleviate various pain conditions. At low concentrations, this non-selective TRPM8 agonist elicits a cooling sensation, however higher concentrations result in cold hyperalgesia in normal subjects and paradoxically analgesia in neuropathic patients. Through behavioural and electrophysiological means, we examined whether this back-translated into a pre-clinical rodent model. ⋯ In addition, M8-Ag attenuated behavioural hypersensitivity to innocuous cooling but not mechanical stimulation. These data suggest that menthol induced hyperalgesia is not consistently replicable in the rat and that the analgesic properties are revealed by injury. Systemic TRPM8 agonists might be beneficial in neuropathy without affecting normal cold sensitivity.
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Chronic pain after peripheral nerve damage is often accompanied by a reduction in prefrontal cortex (PFC)-related cognitive functions, which are regulated by noradrenaline, released from efferents originating in the locus coeruleus (LC). L5 to L6 spinal nerve ligation (SNL) in rats increased tissue content and extracellular concentrations of noradrenaline in microdialysates from the PFC, and impaired attentional level in the novel object recognition test. Systemic gabapentin, commonly used to treat chronic pain, impaired the novel object recognition task in normal but not SNL animals. ⋯ In contrast, locally perfused gabapentin reduced noradrenaline release in the PFC in vivo and in PFC synaptosomes in vitro. SNL- and gabapentin-induced impairment of novel object recognition task were reversed by intraperitoneal injection of the α1-adrenoceptor antagonist prazosin. These results suggest that increase in noradrenergic tone, induced by nerve injury or gabapentin, impairs PFC functions possibly via α1-adrenoceptor-mediated mechanisms; that the net effect of gabapentin on noradrenaline release in the PFC would depend on sometimes opposing actions at different sites; and that nerve injury selectively impairs the response to gabapentin in PFC-projecting neurons in the LC.