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Background: Injury to the trigeminal nerve often results in the development of chronic pain states including tactile allodynia, or hypersensitivity to light touch, in orofacial area, but its underlying mechanisms are poorly understood. Peripheral nerve injury has been shown to cause up-regulation of thrombospondin-4 (TSP4) in dorsal spinal cord that correlates with neuropathic pain development. In this study, we examined whether injury-induced TSP4 is critical in mediating orofacial pain development in a rat model of chronic constriction injury to the infraorbital nerve., Methods: Orofacial sensitivity to mechanical stimulation was examined in a unilateral infraorbital nerve ligation rat model. The levels of TSP4 in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 spinal cord (Vc/C2) from injured rats were examined at time points correlating with the initiation and peak orofacial hypersensitivity. TSP4 antisense and mismatch oligodeoxynucleotides were intrathecally injected into injured rats to see if antisense oligodeoxynucleotide treatment could reverse injury-induced TSP4 up-regulation and orofacial behavioural hypersensitivity., Results: Our data indicated that trigeminal nerve injury induced TSP4 up-regulation in Vc/C2 at a time point correlated with orofacial tactile allodynia. In addition, intrathecal treatment with TSP4 antisense, but not mismatch, oligodeoxynucleotides blocked both injury-induced TSP4 up-regulation in Vc/C2 and behavioural hypersensitivity., Conclusions: Our data support that infraorbital nerve injury leads to TSP4 up-regulation in trigeminal spinal complex that contributes to orofacial neuropathic pain states. Blocking this pathway may provide an alternative approach in management of orofacial neuropathic pain states., (© 2013 European Pain Federation - EFIC®)

Background: Emotions form an important component in the expression and manifestation of pain. This study tested whether emotionally loaded visual and gustatory conditioning stimuli could influence experimental jaw muscle pain., Patients and Methods: Thirty-one healthy subjects participated in this study. In two sessions, experimental jaw muscle pain was evoked by injection of hypertonic saline (HS) into the masseter muscle. In the first session, jaw muscle pain was conditioned by positive, negative or neutral pictures. In the next session, jaw muscle pain was conditioned by sweet, bitter or tasteless gelatine in the mouth. The subjects continuously rated pain intensity as well as mood and unpleasantness/pleasantness of the conditioning stimuli. As a control experiment, the same design was applied in eight subjects using painful thermal stimuli., Results: HS evoked moderate levels of pain in all subjects. During conditioning with negatively loaded pictures, HS-evoked pain was higher compared with neutral and positive pictures (p = 0.002). There was a significant correlation between negative emotional scores linked to the pictures and HS-evoked pain intensity (r = 0.404, p = 0.021). No effects on HS-evoked pain intensity were observed during positive pictures or during sweet or bitter gustatory stimuli. The latter may be due to failure of the gustatory stimuli to generate changes in emotional scores. No significant effects were observed on thermal pain sensitivity., Conclusion: These results suggest that not all conditioning stimuli are potent modifiers of emotions, which seems to be a prerequisite for effects on muscle pain perception., (© 2012 European Federation of International Association for the Study of Pain Chapters.)

Recent studies suggest that CNS phospholipase A(2) (PLA(2) ) isoforms play a role in nociception, but until now, direct evidence of increased brain PLA(2) activity during allodynia or hyperalgesia is lacking. The present study was carried out, using lipidomics or systems wide analyses of lipids using tandem mass spectrometry, to elucidate possible changes in rat brain lipids after inflammatory pain induced by facial carrageenan injection. The caudal medulla oblongata showed decreases in phospholipids including phosphatidylethanolamine and phosphatidylinositol species, but increases in lysophospholipids, including lysophosphatidylethanolamine, lysophosphatidylinositol and lysophosphatidylserine, indicating increased PLA(2) activity and release of arachidonic acid after facial carrageenan injection. These changes likely occur in the spinal trigeminal nucleus which relays nociceptive input from the orofacial region. High levels of sPLA(2) -III, sPLA(2) -XIIA, cPLA(2) and iPLA(2) mRNA expression were detected in the medulla oblongata. Increase in sPLA(2) -III mRNA expression was found in the caudal medulla of carrageenan-injected rats, although no difference in sPLA(2) -III protein expression was detected. The changes in lipids as determined by lipidomics were therefore consistent with an increase in PLA(2) enzyme activity, but no change in enzyme protein expression. Together, these findings indicate enhanced PLA(2) activity in the caudal medulla oblongata after inflammatory orofacial pain., (© 2011 European Federation of International Association for the Study of Pain Chapters.)

Orofacial pain disorders are frequent in the general population and their pharmacological treatment is not always adequately resolved. Cannabinoids have demonstrated their analgesic effect in several pain conditions, both in animal models and in clinical situations. The aim of the present study was to evaluate the cannabinoid-mediated antinociception in two inflammatory models of orofacial pain (orofacial and temporomandibular joint (TMJ) formalin test) and to compare it with a spinal inflammatory model (paw formalin test). WIN 55,212-2 (0.5, 1mg/kg), a synthetic cannabinoid agonist, was intraperitoneally (i.p.) administered prior to formalin and significantly reduced the nociceptive behavioural responses in these inflammatory tests. To elucidate which subtype of receptor could be involved in such effect, two selective cannabinoid antagonists were administered prior to WIN. SR141716A (1mg/kg i.p.), the CB1 receptor-selective antagonist, was able to prevent the cannabinoid-induced analgesia in all three models, whereas SR144528 (1mg/kg i.p.), the CB2 receptor-selective antagonist, only prevented it in the paw formalin test. A comparison with the antinociceptive effects of morphine (2.5, 5, 10mg/kg, i.p.), indomethacin (2.5, 5mg/kg, i.p.) and ketamine (25, 50mg/kg, i.p.) was also performed. Morphine displayed a dose-dependent reduction of acute and inflammatory pain in all three models, whereas indomethacin and ketamine only attenuated inflammatory pain at the highest tested doses. These results indicate that the cannabinoid-induced antinociception in the orofacial region is mediated by activation of CB1 cannabinoid receptor. Moreover WIN was as effective as morphine and more effective than indomethacin and ketamine, in oral inflammatory pain.

The aim of the study was to investigate the interaction between glutamate and capsaicin in inducing muscle pain and sensitization in humans. Fifteen male volunteers participated. Glutamate or capsaicin or isotonic saline, in a paired-sequence order, was injected randomly into the right or left masseter muscle. Two injections were given in a double-blinded design 25 min apart in 1 session/week over 4 weeks: saline (A1) followed by glutamate (A2), capsaicin (B1) followed by glutamate (B2), saline (C1) followed by capsaicin (C2), and glutamate (D1) followed by capsaicin (D2). The subjects drew the area of perceived pain and scored pain intensity on a 0-10 visual analogue scale (VAS). Pressure pain threshold (PPT) at the injection site, at a site 2-cm away, and on the contralateral side, as well as pressure pain tolerance (PPTol) at the injection site and contralateral site, were also measured before and after injection and subsequently at 5-min intervals. Paired t-test analyses showed that the pain drawing area was significantly smaller in the B2 compared to the A2 condition (P=0.028), and significantly larger in the D2 compared to the C2 condition (P=0.027). It also revealed significantly lower VAS peak pain intensity (P=0.008) and smaller VAS area under the curve (P=0.003) for the B2 compared to the A2 condition, and significantly higher VAS peak pain (P=0.015) and larger VAS area under the curve (P=0.037) for the D2 compared to the C2 condition. There was a significant PPT and PPTol decrease at the injection site after glutamate or capsaicin injection (ANOVA: P<0.028). The percentage decrease in PPT or PPTol (at the injection site) was not significantly different for the B2 compared to the A2 condition (Paired t-test: P>0.682) or for the D2 compared to the C2 condition (P>0.133). Significant PPT changes were also observed at the site 2 cm away, but not on the contralateral side. In conclusion, these findings indicate that intramuscular administrations of glutamate and capsaicin interact and influence pain and sensitization of muscle nociceptors: glutamate causes a sensitization to subsequent administration of capsaicin, whereas capsaicin is associated with a desensitization to subsequent injection of glutamate. These findings support previous animal data.