Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

Abstract

In addition to analgesia, opioids may also produce paradoxical pain amplification [opioid-induced hyperalgesia (OIH)] either on abrupt withdrawal or during continuous long-term application. Here, we assessed antinociceptive and pronociceptive effects of three clinically used opioids at C-fiber synapses in the rat spinal dorsal horn in vivo. During 60 min of intravenous infusions of remifentanil (450), C-fiber-evoked field potentials were depressed and pairedpulse ratios (PPR) were increased, indicating a presynaptic inhibition by all three opioids. After withdrawal, postsynaptic responses were enhanced substantially for the remaining of the recording periods of at least 3 h. Withdrawal from remifentanil led to long-term potentiation (LTP) of synaptic strength in C-fibers via activation of spinal -opioid receptors (MORs) and spinal NMDA receptors (NMDARs). Fentanyl and morphine caused an enhancement of synaptic transmission at C-fibers, which involved two distinct mechanisms: (1) an opioid withdrawal LTP that also required activation of spinal MORs and NMDARs and that was associated with a decrease in PPR suggestive of a presynaptic mechanism of its expression, and (2) an immediate-onset, descending facilitation of C-fiber-evoked field potentials during and after intravenous infusion of fentanyl and morphine. Immediate-onset, descending facilitation was mediated by the activation of extraspinal MORs, descending serotonergic pathways, and spinal 5-hydroxytryptamine-3 receptors (5-HT 3 Rs). Our study identified fundamentally different pronociceptive effects of clinically used opioids and suggests that OIH can be prevented by the combined use of NMDAR and 5-HT 3 R antagonists.

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

“…The paired-pulse ratio (PPR) is defined as the peak amplitude of the second eEPSC (P2) divided by the first eEPSC (P1) evoked by two pulses. The reduction of first eEPSCs by BAM8-22 with ML382 was associated with an increased PPR in MrgprX1 mice, suggesting presynaptic inhibition of excitatory neurotransmitter release (48,49). This phenomenon was not observed in Mrgpr −/− mice, and ML382 alone did not affect PPR.…”

Sobre a analgesia pós-operatória da morfina, cetamina ou da associação em cadelas submetidas à ovariossalpingohisterectomia eletiva

“…nociceptivo dos opioides ocorre por três vias distintas: a) o aumento da transmissão sináptica das fi bras C, por ativação dos receptores opioides Mu e NMDA extraespinhais; b) facilitação da via descendente, com potenciais de ação evocados nas fi bras C, pela ativação dos receptores Mu extraespinhais, na via serotoninérgica descendente; e c) ativação prolongada das fi bras C por ativação dos receptores Mu e NMDA espinhais (HEINL et al, 2011). Neste último estudo, os efeitos pró-nociceptivos após infusão contínua da morfi na, fentanil e remifentanil foram eliminados pela administração de antagonistas NMDA, o que pode justifi car em nosso estudo o melhor desempenho analgésico dos animais tratados com cetamina e morfi na, quando comparado à morfi na isoladamente.…”

5-HT7 receptor activation: A novel target for treatment of opioid-induced hyperalgesia – A hypothesis and mini review

“…5-HT receptor subtypes mediating its effect and the pathophysiological status of the animal also play role in these dual actions of 5-HT. 31 Serotonin receptor antagonists induced hyperalgesia without preventing morphine antinociception; 1 moreover, 5-HT3 receptors has been shown to mediate descending pain facilitation and pronociceptive effects of opioids, 10,16 pointing to the role of 5-HT receptor subtypes in opiod action and hyperalgesia. Recent research is focusing on 5-HT7 receptors, and this receptor system has been implicated in circadian rhythm, nociception, thermoregulation, memory, anxiety, depression and schizophrenia.…”