Pain and stress: functional evidence that supra-spinal mechanisms involved in pain-induced analgesia mediate stress-induced analgesia.

Analgesia induced by stressful and painful stimuli is an adaptive response during life-threatening situations. There is no evidence linking the mechanisms underlying them, while the former depends on the activation of stress-related brain pathways, the second depends on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. In this study, we hypothesized that stress-induced analgesia is also dependent on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. We used immobilization, a classical procedure to induce acute stress, and evaluated its ability to decrease the nociceptive responses induced either by carrageenan or by formalin in rats. Immobilization stress significantly decreased either carrageenan-induced hyperalgesia or formalin-induced tonic nociception in a time-dependent manner. This stress-induced analgesia is similar to pain-induced analgesia, as revealed by contrasting the antinociceptive effect induced by immobilization and by a forepaw injection of capsaicin. The administration of a µ-opioid receptor antagonist (CTOP, 0.5 µg) into the nucleus accumbens, as well as that of a nicotinic cholinergic receptor antagonist (mecamylamine, 0.6 µg) into the rostral ventromedial medulla, blocked immobilization stress-induced analgesia in both pain models. These results demonstrate that supraspinal mechanisms which are known to mediate pain-induced analgesia also mediate stress-induced analgesia. Therefore both forms of analgesia have overlapping mechanisms, probably recruited in response to the perception of danger.

N-palmitoylethanolamide in the anterior cingulate cortex attenuates inflammatory pain behaviour indirectly via a CB1 receptor-mediated mechanism.

The neural substrates and mechanisms mediating the antinociceptive effects of the endogenous bioactive lipid, N-palmitoylethanolamide (PEA), require further investigation. We investigated the effects of exogenous PEA administration into the anterior cingulate cortex (ACC), an important brain region linked with cognitive and affective modulation of pain, on formalin-evoked nociceptive behaviour in rats. Potential involvement of peroxisome proliferator-activated receptor isoforms (PPAR) α and γ or endocannabinoid-mediated entourage effects at cannabinoid1 (CB1) receptors or transient receptor potential subfamily V member 1 (TRPV1) in mediating the effects of PEA was also investigated. Intra-ACC administration of PEA significantly attenuated the first and early second phases of formalin-evoked nociceptive behaviour. This effect was attenuated by the CB1 receptor antagonist AM251, but not by the PPARα antagonist GW6471, the PPARγ antagonist GW9662, or the TRPV1 antagonist 5'-iodo resiniferatoxin. All antagonists, administered alone, significantly reduced formalin-evoked nociceptive behaviour, suggesting facilitatory/permissive roles for these receptors in the ACC in inflammatory pain. Post-mortem tissue analysis revealed a strong trend for increased levels of the endocannabinoid anandamide in the ACC of rats that received intra-ACC PEA. Expression of c-Fos, a marker of neuronal activity, was significantly reduced in the basolateral nucleus of the amygdala, but not in the central nucleus of the amygdala, the rostral ventromedial medulla or the dorsal horn of the spinal cord. In conclusion, these data indicate that PEA in the ACC can reduce inflammatory pain-related behaviour, possibly via AEA-induced activation of CB1 receptors and associated modulation of neuronal activity in the basolateral amygdala.