The effects of serotonin/norepinephrine reuptake inhibitors and serotonin receptor agonist on morphine analgesia and tolerance in rats

Abstract

Several studies have demonstrated that serotonergic and noradrenergic systems have important roles in morphine analgesia and tolerance. However, the exact mechanism underlying the development of morphine tolerance is not fully understood. The aim of this study was to investigate the possible role of serotonin/norepinephrine reuptake inhibitors (amitriptyline, venlafaxine) and serotonin receptor (5-HT(1A) and 5-HT(1B/1D)) agonist (dihydroergotamine) in morphine analgesia and tolerance in rats. To constitute morphine tolerance, animals received morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of amitriptyline (20 mg/kg; i.p.), venlafaxine (20 mg/kg; s.c.), dihydroergotamine (100 μg/kg; i.v.) and morphine (5 mg/kg) were considered at 15- to 30-min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. In this study, the data obtained suggested that amitriptyline and venlafaxine significantly increased the analgesic effect of morphine and attenuated the expression of morphine tolerance. However, dihydroergotamine significantly increased the analgesic effect of morphine but did not reduce the expression of morphine tolerance. In conclusion, we determined that co-administration of morphine with amitriptyline and venlafaxine increased the analgesic effects of morphine and attenuated the morphine analgesic tolerance.

The pathophysiological role of serotonin receptor systems in opioid analgesia and tolerance

“…For example, coadministration of fluoxetine, amitriptyline and zimelidine (selective 5-HT uptake inhibitors) with morphine prevents the morphine analgesic tolerance. 17,116 Conversely, administered with either 1-tryptophan, the 5-HT precursor, accelerates the development of morphine tolerance. 117 These conflicting findings could probable caused by a distinct in 5-HT density in different synapses.…”

“…These agents include: nitric oxide (NO) synthase inhibitors, calcium channel blockers, substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, cyclooxygenase (COX) inhibitors, antagonists of the NMDA (N-methyl-D-aspartate) receptor, cholecystokinin (CCK) receptor antagonists, and 5-HT receptor agonists. [8][9][10][11][12][13][14][15][16][17] Serotonergic neurons are involved in the formation of spinal cord pain. 18 Stimulation of serotonergic neurons decreases the pain responses through a descending inhibitory pathway in the spinal cord dorsal horn.…”

Effect of the extract of Hypericum perforatum on neurodevelopment of regions related to pain control and convulsion

“…The anticonvulsant effect is due to the activation of receptors for opioids and serotonin (5-HT), but mainly through activation of receptors for γ-aminobutyric acid (GABA), primarily located in the hippocampus (Hosseinzadeh et al, 2005;Ivetic et al, 2011). The antinociceptive effect results from activation of receptors for GABA, opioids, and 5-HT in both gray periaqueducal area (CPA), and in the spinal cord, besides inhibiting the release of nociceptive mediators associated with inflammation (Uchida et al, 2008;Ozdemir et al, 2012).…”

The Symptom Cluster-Based Approach to Individualize Patient-Centered Treatment for Major Depression

“…34 Pain is thought to be mediated by both the serotonin and norepinephrine pathways acting directly to potentiate the pain-killing effects of the endogenous opioid system. 55 Understanding how these core symptoms are related to deficiencies in specific neurotransmitters is the first step to choosing the most appropriate types of antidepressants for each symptom cluster.…”

“…Pain is thought to be mediated by both serotonin and norepinephrine acting directly to potentiate the analgesic effects of the endogenous opioid system. 55 Since deficiencies of both serotonin and norepinephrine are present, it is logical to recommend an SNRI. Duloxetine is NaSSA, noradrenergic specific serotonergic antidepressant; NDRI, norepinephrine dopamine reuptake inhibitor; SARI, serotonin antagonist reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.…”