Acquisition of analgesic properties by the cholecystokinin (CCK)/CCK2 receptor system within the amygdala in a persistent inflammatory pain condition

Abstract

Pain is associated with negative emotions such as anxiety, but the underlying neurocircuitry and modulators of the association of pain and anxiety remain unclear. The neuropeptide cholecystokinin (CCK) has both pronociceptive and anxiogenic properties, so we explored the role of CCK in anxiety and nociception in the central amygdala (CeA), a key area in control of emotions and descending pain pathways. Local infusion of CCK into the CeA of control rats increased anxiety, as measured in the light–dark box test, but had no effect on mechanical sensitivity. By contrast, intra-CeA CCK infusion 4 days after Complete Freund's Adjuvant (CFA) injection into the hindpaw resulted in analgesia, but also in loss of its anxiogenic capacity. Inflammatory conditions induced changes in the CeA CCK signaling system with an increase of CCK immunoreactivity and a decrease in CCK1, but not CCK2, receptor mRNA. In CFA rats, patch-clamp experiments revealed that CCK infusion increased CeA neuron excitability. It also partially blocked the discharge of wide dynamic range neurons in the dorsal spinal cord. These effects of CCK on CeA and spinal neurons in CFA rats were mimicked by the specific CCK2 receptor agonist, gastrin. This analgesic effect was likely mediated by identified CeA neurons projecting to the periaqueductal gray matter that express CCK receptors. Together, our data demonstrate that intra-CeA CCK infusion activated a descending CCK2 receptor-dependent pathway that inhibited spinal neuron discharge. Thus, persistent pain induces a functional switch to a newly identified analgesic capacity of CCK in the amygdala, indicating central emotion-related circuit controls pain transmission in spinal cord.

<p>Rediscovery of Ceruletide, a CCK Agonist, as an Analgesic Drug</p>

“…The debate of the analgesic mechanism of action of CRL via central or peripheral mechanisms still needs to be addressed, although there are studies that suggest that both mechanisms could contribute to analgesia, and the central role of the CCK system situated in the amygdala has recently been highlighted. 39 Given the poverty of our therapeutic armamentarium for the treatment of chronic cancer pain, it seems to us that the absence of further interest in the use of CRL in this indication could be a missed opportunity. As CRL is a non-opioid peptide and does not act directly via the opiate receptors, a role as an intrathecal infusion against cancer pain in palliation seems worthwhile to explore, especially since some of the complications of intrathecal morphine delivery might be avoided such as tip of catheter granuloma and pH issues.…”

“…These recent findings also support further exploration of CRL as an analgesic compound. 39 Further studies might be warranted to confirm the mechanisms and underlie the intracellular pathways involved with CRL and CCK effects.…”

OralLactobacillus reuteriLR06 orBifidobacteriumBL5b supplement do not produce analgesic effects on neuropathic and inflammatory pain in rats

“…To induce inflammatory pain, rats received 100 µl subcutaneous (s.c.) injection of complete Freund's adjuvant (Sigma, USA) into the left hind paw. Saline was used for the vehicle sham groups (Roca‐Lapirot et al, ). The animals were randomly assigned to experimental groups, untreated or probiotically treated, and submitted to behavioral tests every two days, and body weight (g) was measured before every behavioral test.…”

Methylene Blue Application to Lessen Pain: Its Analgesic Effect and Mechanism

“…There are some links between TLR4, OR, and cholecystokinin (CCK). CCK, an important neurohormone, plays a variety of roles in the nervous system and notably engaged in pain reduction mainly via CCK-B receptors (Roca-Lapirot et al, 2019;Keppel Hesselink, 2020). Interestingly, this peptide functions to inhibit OR activity and thus reduces the morphine-induced antinociception (Torres-López et al, 2007;Yang et al, 2018).…”