The journal of pain : official journal of the American Pain Society
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Although joint pain is common, its mechanisms remain undefined, with little known about the spinal neuronal responses that contribute to this type of pain. Afferent activity and sustained spinal neuronal hyperexcitability correlate to facet joint loading and the extent of behavioral sensitivity induced after painful facet injury, suggesting that spinal neuronal plasticity is induced in association with facet-mediated pain. This study used a rat model of painful C6-C7 facet joint stretch, together with intrathecal administration of gabapentin, to investigate the effects of one aspect of spinal neuronal function on joint pain. Gabapentin or saline vehicle was given via lumbar puncture prior to and at 1 day after painful joint distraction. Mechanical hyperalgesia was measured in the forepaw for 7 days. Extracellular recordings of neuronal activity and astrocytic and microglial activation in the cervical spinal cord were evaluated at day 7. Gabapentin significantly (P = .0001) attenuated mechanical hyperalgesia, and the frequency of evoked neuronal firing also significantly decreased (P < .047) with gabapentin treatment. Gabapentin also decreased (P < .04) spinal glial fibrillary acidic protein expression. Although spinal Iba1 expression was doubled over sham, gabapentin did not reduce it. Facet joint-mediated pain appears to be sustained through spinal neuronal modifications that are also associated with astrocytic activation. ⋯ Intrathecal gabapentin treatment was used to investigate behavioral, neuronal, and glial response in a rat model of painful C6-C7 facet joint stretch. Gabapentin attenuated mechanical hyperalgesia, reduced evoked neuronal firing, and decreased spinal astrocytic activation. This study supports that facet joint pain is sustained through spinal neuronal and astrocytic activation.
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Previous studies have reported that the intrathecal (i.t.) administration of transforming growth factor β1 (TGF-β1) prevents and reverses neuropathic pain. However, only limited information is available regarding the possible role and effects of spinal TGF-β1 in neuropathic pain. We aimed to investigate the antinociceptive effects of exogenous TGF-β1 on chronic constriction injury (CCI)-induced neuropathic pain in rats. We demonstrated that sciatic nerve injury caused a downregulation of endogenous TGF-β1 levels on the ipsilateral side of the lumbar spinal dorsal gray matter, and that the i.t. administration of TGF-β1 (.01-10 ng) significantly attenuated CCI-induced thermal hyperalgesia in neuropathic rats. TGF-β1 significantly inhibited CCI-induced spinal neuroinflammation, microglial and astrocytic activation, and upregulation of tumor necrosis factor-α. Moreover, i.t. TGF-β1 significantly attenuated the CCI-induced downregulation of glutamate transporter 1, the glutamate aspartate transporter, and the excitatory amino acid carrier 1 on the ipsilateral side. Furthermore, i.t. TGF-β1 significantly decreased the concentrations of 2 excitatory amino acids, aspartate and glutamate, in the spinal dialysates in CCI rats. In summary, we conclude that the mechanisms of the antinociceptive effects of i.t. TGF-β1 in neuropathy may include attenuation of spinal neuroinflammation, attenuation, or upregulation of glutamate transporter downregulation, and a decrease of spinal extracellular excitatory amino acids. ⋯ Clinically, medical treatment is usually initiated after the onset of intractable pain. Therefore, in the present study, i.t. TGF-β1 was designed to be administered 2 weeks after the establishment of CCI pain. Compared to the continuous TGF-β1 infusion mode, single-dose administration seems more convenient and practical to use.
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The ventrolateral periaqueductal gray (vlPAG) contributes to morphine antinociception and tolerance. Chronic inflammatory pain causes changes within the PAG that are expected to enhance morphine tolerance. This hypothesis was tested by assessing antinociception and tolerance following repeated microinjections of morphine into the vlPAG of rats with chronic inflammatory pain. Microinjection of morphine into the vlPAG reversed the allodynia caused by intraplantar administration of complete Freund's adjuvant and produced antinociception on the hot plate test. Although there was a gradual decrease in morphine antinociception with repeated testing, there was no evidence of tolerance when morphine- and saline-treated rats with hind paw inflammation were tested with cumulative doses of morphine. In contrast, repeated morphine injections into the vlPAG caused a rightward shift in the morphine dose-response curve in rats without hind paw inflammation, as would be expected with the development of tolerance. The lack of tolerance in complete Freund's adjuvant-treated rats was evident whether rats were exposed to repeated behavioral testing or not (experiment 2) and whether they were treated with 4 or 8 prior microinjections of morphine into the vlPAG (experiment 3). These data demonstrate that chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does disrupt the development of tolerance. ⋯ The present data show that induction of chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does attenuate the development of tolerance. This finding indicates that tolerance to opioids in rats with inflammatory pain is mediated by structures other than the vlPAG.
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Inactivation of transient receptor potential vanilloid-1 (TRPV1) receptors is one approach to analgesic drug development. However, TRPV1 receptors exert different effects on each modality of pain. Because muscle pain is clinically important, we compared the effect of TRPV1 ligands on musculoskeletal nociception to that on thermal and tactile nociception. Injected parenterally, capsaicin had no effect on von Frey fiber responses (tactile) but induced a transient hypothermia and hyperalgesia in both the tail flick (thermal) and grip force (musculoskeletal) assays, presumably by its agonistic action at TRPV1 sites. In contrast, resiniferatoxin (RTX) produced a chronic (>58 days) thermal antinociception, consistent with its reported ability to desensitize TRPV1 sites. In the same mice, RTX produced a transient hypothermia (7 hours) and a protracted (28-day) musculoskeletal hyperalgesia in spite of a 35.5% reduction in TRPV1 receptor immunoreactivity in muscle afferents. Once musculoskeletal hyperalgesia subsided, mice were tolerant to the hyperalgesic effects of either capsaicin or RTX whereas tolerance to hypothermia did not develop until after 3 injections. Musculoskeletal hyperalgesia was prevented but not reversed by SB-366791, a TRPV1 antagonist, indicating that TRPV1 receptors initiate but do not maintain hyperalgesia. Injected intrathecally, RTX produced only a brief musculoskeletal hyperalgesia (2 days), after which mice were tolerant to this effect. ⋯ The effect of TRPV1 receptors varies depending on modality and tissue type, such that RTX causes thermal antinociception, musculoskeletal hyperalgesia, and no effect on tactile nociception in healthy mice. Spinal TRPV1 receptors are a potential target for pain relief as they induce only a short musculoskeletal hyperalgesia followed by desensitization.