Conolidine: A Novel Plant Extract for Chronic Pain

: Pain, the most common symptom reported among patients in the primary care setting, is complex to manage. Opioids are among the most potent analgesics agents for managing pain. Since the mid-1990s, the number of opioid prescriptions for the management of chronic non-cancer pain (CNCP) has increased by more than 400%, and this increased availability has significantly contributed to opioid diversion, overdose, tolerance, dependence, and addiction. Despite the questionable effectiveness of opioids in managing CNCP and their high rates of side effects, the absence of available alternative medications and their clinical limitations and slower onset of action has led to an overreliance on opioids. Conolidine is an indole alkaloid derived from the bark of the tropical flowering shrub Tabernaemontana divaricate used in traditional Chinese, Ayurvedic, and Thai medicine. Conolidine could represent the beginning of a new era of chronic pain management. It is now being investigated for its effects on the atypical chemokine receptor (ACK3). In a rat model, it was found that a competitor molecule binding to ACKR3 resulted in inhibition of ACKR3’s inhibitory activity, causing an overall increase in opiate receptor activity. Although the identification of conolidine as a potential novel analgesic agent provides an additional avenue to address the opioid crisis and manage CNCP, further studies are necessary to understand its mechanism of action and utility and efficacy in managing CNCP.

Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents

Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.

Opioids depress breathing through two small brainstem sites

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose—opioid respiratory depression. Here, we identify two primary changes to breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which we confirm by locally eliminating the μ-Opiate receptor. We find the critical brain site is the origin of the breathing rhythm, the preBötzinger Complex, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

Evidence for the presence of morphine like substance and μ opiate receptor expression in Dicrocoelium dendriticum (Trematoda: Dicrocoeliidae)

Parasites for living in host’s body, evade from host’s immune system using variant methods such as production of some molecules with immunosuppressive properties. Of these immunosuppression molecules are morphine and morphine like substances. It can effect on innate and adaptive immunity and also humoral and cellular immunity. The past researches were approved the existence of morphine in the brain and adrenal of beef and in brain of mammalian and also it has been demonstrated as an immune modulator molecule in some invertebrates, some of the nematodes and also a trematode Schistosoma mansoni, But there is no document for morphine evidence in trematode Dicrocoelium dendriticum. Infection with this trematode has much importance either in health of ruminant and economic loos in the meat industry. In addition, this trematode is a zoonosis that there is no proper treatment for it in contrast with the other liver fluke, Fasciola hepatica. We assume that living for a long time in the bile ducts of host is related to morphine like substance as an immune regulatory molecule. We use RP-HPLC method for detection morphine in D. dendriticum and also using reverse transcription polymerase chain reaction (RT-PCR) for μ opioid receptor finding. According to the results D. dendriticum has endogenous morphine like material and also the existence of opioid μ receptor in this trematode was approved. Living in host bile duct for a long time without sever immunopathologycal impact, suggested that probably this worm use of morphine like material as an immunoregulatory molecule and also for escaping from host immune system.

Naloxone’s Effect on Activity-Induced Phase Shifts of Circadian Rhythms

Vigorous running in a novel exercise wheel by hamsters during the subjective day results in large (about 3 hr) phase advances of their circadian rhythms. We administered the opiate receptor antagonist naloxone at 10 mg/kg and 20 mg/kg (i.p.) and found that at 20 mg/kg it significantly reduced phase shifts. This dose of naloxone also reduced the amount of running shown by hamsters in the novel wheel. At the 20 mg/kg dose, the reduced amount of running resulted in smaller phase shifts. The results are consistent with the hypothesis that nonphotic phase shifts are linked to exercise and arousal in hamsters. However, because high amounts of running were accompanied by phase shifting in animals whose opiate receptors were blocked, the results provide no evidence that the rewarding nature of running in rodents is an important causal factor in nonphotic phase shifting beyond its role in promoting running.