The journal of pain : official journal of the American Pain Society
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Changes in serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and γ-aminobutyric acid (GABA) levels in the spinal cord are known to occur in response to nociceptive stimuli, yet little research has examined possible underlying sex differences in these changes and how they might affect nociception. We have used pharmacological approaches in a well established model of tonic nociception, the formalin test, to explore the effects of altering neurotransmitter levels on nociceptive responses in male and female C57BL/6 mice. The monoamine oxidase (MAO) inhibitor phenelzine (PLZ), its metabolite phenylethylidenehydrazine (PEH), and a derivative compound of PLZ, N(2)-acetylphenelzine (N(2)-AcPLZ), were used to increase endogenous levels of: GABA, 5-HT, and NA (PLZ); GABA alone (PEH); or 5-HT and NA only (N(2)-AcPLZ). Although both sexes had a reduction in second phase nociceptive behaviors with PEH pretreatment, the analgesic effect of PLZ was only observed in male mice. High performance liquid chromatography analysis revealed male mice had greater spinal cord increases in 5-HT and NA levels compared with female mice. Female mice, in contrast, had greater increases in GABA levels with pretreatments. With N(2)-AcPLZ pretreatment, only male mice had a reduction in second phase nociceptive behaviors despite similar increases in 5-HT and NA levels in both sexes. These findings suggest that male mice may utilize serotonergic and noradrenergic pathways more efficiently for the attenuation of nociceptive behavior and female mice are more dependent on alternate mechanisms. To our knowledge, these findings are the first on the antinociceptive properties of altering 5-HT, NA, and GABA levels with the MAO inhibitor PLZ and its derivatives in a model of tonic pain processing. They also reveal significant underlying sex differences associated with these treatments. ⋯ The present study found that nociception in male and female mice may be regulated by different neurotransmitter systems. These results indicate that different pharmacological approaches may be needed to treat pain in both sexes.
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Epidemiological studies and meta-analyses report a strong relationship between chronic pain and abnormalities in glucose metabolism, but the exact relationship between chronic pain and insulin resistance in type 2 diabetes (T2D) remains unknown. Using a model of neuropathic thermal and tactile hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve in Zucker Diabetic Fatty (ZDF) and Zucker Lean (ZL) littermates, we compared the recovery period of hypersensitivity and the progression of T2D and studied the possible involvement of insulin receptors (IRs) in the comorbidity of these 2 conditions. We found that the nociceptive thresholds to thermal and mechanical stimulation in naive ZDF rats were lower than in ZL littermates at 6 weeks of age. Although ZDF and ZL rats developed thermal and tactile hypersensitivity after CCI, it took a longer time nociceptive sensitivity to be restored in ZDF rats. Nerve injury accelerated the progression of T2D in ZDF rats, shown by an earlier onset of hyperglycemia, more severe hyperinsulinemia, and a higher concentration of glycosylated hemoglobin Alc 6 weeks after CCI, compared with those in naive ZDF and ZL rats. IR-immunoreactive cells were located across the central nervous system and skeletal muscles. In the central nervous system, IR coexpressed with a neuronal marker (neuronal nuclei) but not a glial marker (glial fibrillary acidic protein). There was a low level of IR expression in skeletal muscles of naive ZDF rats. In contrast, CCI reduced the IR expression in skeletal muscles as well as the ipsilateral spinal cord, primarily in the dorsal horn. In conclusion, our data suggest that the relationship between insulin resistance and chronic pain in ZDF rats is bidirectional and an impaired IR signaling system might be implicated in this reciprocal relationship. ⋯ Nerve injuries in genetically susceptible individuals might accelerate the development of insulin resistance as in T2D. A downregulated expression of IRs in the skeletal muscle innervated by the injured nerve is one of the underlying mechanisms.