Abstract
BackgroundA hallmark of many orofacial pain disorders is cold sensitivity, but relative to heat-related pain, mechanisms of cold perception and the development of cold allodynia are not clearly understood. Molecular mediators of cold sensation such as TRPM8 have been recently identified and characterized using in vitro studies. In this study we characterized operant behavior with respect to individually presented cold stimuli (24, 10, 2, and -4°C) and in a thermal preference task where rats chose between -4 and 48°C stimulation. We also evaluated the effects of menthol, a TRPM8 agonist, on operant responses to cold stimulation (24, 10, and -4°C). Male and female rats were trained to drink sweetened milk while pressing their shaved faces against a thermode. This presents a conflict paradigm between milk reward and thermal stimulation.ResultsWe demonstrated that the cold stimulus response function was modest compared to heat. There was a significant effect of temperature on facial (stimulus) contacts, the ratio of licking contacts to stimulus contacts, and the stimulus duration/contact ratio. Males and females differed only in their facial contacts at 10°C. In the preference task, males preferred 48°C to -4°C, despite the fact that 48°C and -4°C were equally painful as based on their reward/stimulus and duration/contact ratios. We were able to induce hypersensitivity to cold using menthol at 10°C, but not at 24 or -4°C.ConclusionOur results indicate a strong role for an affective component in processing of cold stimuli, more so than for heat, which is in concordance with human psychophysical findings. The induction of allodynia with menthol provides a model for cold allodynia. This study provides the basis for future studies involving orofacial pain and analgesics, and is translatable to the human experience.
Highlights
A hallmark of many orofacial pain disorders is cold sensitivity, but relative to heatrelated pain, mechanisms of cold perception and the development of cold allodynia are not clearly understood
The hindpaw acetone cooling assay [1,2] has been used to evaluate cold allodynia, but this test is difficult to quantify in terms of the temperature delivered, and it is difficult to separate the mechanical sensation of wetness from the onset of skin cooling
For mildly aversive (10°C) cold stimulation, males were hindered from completing the task, as revealed by less licking and more stimulus contacts that did not progress to licking
Summary
A hallmark of many orofacial pain disorders is cold sensitivity, but relative to heatrelated pain, mechanisms of cold perception and the development of cold allodynia are not clearly understood. Male and female rats were trained to drink sweetened milk while pressing their shaved faces against a thermode This presents a conflict paradigm between milk reward and thermal stimulation. Allchorne et al demonstrated a stimulus-response function to cold stimulation using a peltier device and recorded hindpaw withdrawal latency as the outcome measure in freely moving animals [3]. This method is more quantifiable than the acetone assay and does not involve restraint-related stress; this reflex-based assay provides limited information regarding evaluation of the central processing of pain. Mauderli et al [4] and Vierck et al [5] assessed escape latency and duration in an operant assay and found that escape duration revealed stimulus-response relationships better than latency, and the animals were more sensitive to increasing heat than to increasing cold for stimulation of the plantar surfaces of the paws
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