5-HT1A Receptor Agonists Cause Profound Analgesia Comparable to High Doses of Opioids

[rocknroll714]

See these studies:

Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain.

Previously, we have reported that in rat models of chronic pain, in particular, the very-high-efficacy 5-HT(1A) agonist F 13640 induces unprecedented pain relief by novel neuroadaptative mechanisms that involve inverse tolerance and cooperation with nociceptive stimulation in producing analgesia. The present studies detailed the actions of F 13640 and other compounds in the formalin model of tonic nociceptive pain. Intraperitoneal injection of F 13640 (0.01-2.5 mg/kg; t -15 min) caused a dose-dependent and complete inhibition of the paw elevation and paw licking that occurred both early (0-5 min) and late (22.5-27.5 min) after the intraplantar injection of diluted formaldehyde (2.5%) in the rat. The extent to which F 13640 and other 5-HT(1A) receptor ligands inhibited these pain behaviors correlated (p < 0.05) with the extent to which they activated 5-HT(1A) receptors. Under similar conditions, some inhibitory effects were also observed with various agents that are known to produce analgesia by different peripheral and/or central mechanisms (e.g., opioids, NA/5-HT reuptake inhibitors, COX-2 inhibitors and other nonsteroidal anti-inflammatory drugs, gabapentin, and ABT-594). However, with the possible exception of morphine, the effects of all of these agents at nontoxic doses were lower than those of F 13640, in particular in inhibition of early paw elevation. The 5-HT(1A) antagonist WAY 100635, but not naloxone, antagonized the actions of F 13640. These results help to establish large-magnitude 5-HT(1A) receptor activation as a new molecular mechanism of profound, central analgesia and suggest that F 13640 may be particularly effective against pain arising from severe tonic nociceptive stimulation.

The novel analgesic and high-efficacy 5-HT1A receptor agonist F 13640 inhibits nociceptive responses, wind-up, and after-discharges in spinal neurons and withdrawal reflexes.

Evidence shows that serotonin (5-HT) is involved in the transmission of nociception in the central nervous system...we examined the actions of the novel analgesic and high-efficacy 5-HT1A receptor agonist F 13640 as well as those of the opioid receptor agonist fentanyl...Like that of 0.02 mg/kg fentanyl, intraperitoneal injection of 0.31 mg/kg of F 13640 markedly inhibited nociceptive pinch-evoked responses...and repeated (3 Hz) electrical stimulation...The inhibitory effects of F 13640 and fentanyl [on nociception]...were reversed by the specific antagonists WAY 100635 and naloxone, respectively, further indicating that this 5-HT1A receptor-modulated anti-nociception is mu-opioid receptor independent...this suggests that serotonin, through 5-HT1A receptors, exerts an inhibitory role in the control of obstinate pathological pain.

Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia.

We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.

5-HT(1A) receptor activation: new molecular and neuroadaptive mechanisms of pain relief.

Guided by an understanding of signal transduction in pain-processing systems, high-efficacy 5-hydroxytryptamine (5HT)1A receptor activation, by means of F-13640, has been discovered as a new molecular mechanism of pain relief in laboratory animals, inducing two neuroadaptive phenomena. Firstly, this activation cooperates with nociceptive stimulation, paradoxically causing analgesia, and secondly, inverse tolerance develops so that the resulting analgesia grows rather than decays. As an apparent result of these novel neuroadaptive mechanisms, F-13640 exerts an analgesic action in rat models of acute, tonic and chronic nociceptive pain that is rivaled only by large doses of high-efficacy mu-opioid receptor agonists. In models of neuropathic allodynia of peripheral or central origin, chronic F-13640 administration causes an analgesia that surpasses that observed with morphine or other agents exemplifying other central nervous system drug mechanisms of pain relief (e.g., ketamine, imipramine and gabapentin). Indeed, F-13640 produces long-lasting, preemptive and, most remarkably, curative-like actions in neuropathic allodynia. Although awaiting proof-of-concept evidence in humans, high-efficacy 5-HT(1A) receptor activation may uniquely challenge the opioids for pain therapy.

Tolerance and inverse tolerance to the hyperalgesic and analgesic actions, respectively, of the novel analgesic, F 13640.

5-HT(1A) receptor activation by the very-high-efficacy, selective 5-HT(1A) receptor agonist F 13640...was recently discovered to constitute a novel central mechanism of broad-spectrum analgesia that, remarkably, grows rather than decays with chronicity. However, in rodents not exposed to nociception, F 13640 induces its analgesic effect only after having initially induced hyperalgesia. Numerical simulations implementing a signal transduction theory here show that the progressive increase in the intensity of nociceptive stimulation which F 13640 presumably mimics should eventually produce a large analgesic effect without initially causing marked pain...The infusion of increasing (0.04-0.63 mg/rat/day) doses of F 13640 over a 5-week period induced a large analgesia preceded by a hyperalgesic effect that was small and comparable to that induced by initial exposure to a low, 0.04 mg/rat/day dose...Producing the mirror opposite of morphine's neuroadaptive actions, F 13640 causes an analgesia that becomes more powerful with chronic administration, and this at the expense of the initial hyperalgesia which it may also produce.

I doubt it's actually "inverse tolerance" by any means, as the 5-HT1A receptor doesn't upregulate in response to agonization to my knowledge. It's likely just 5-HT1A autoreceptor desenisitzation, which would facilitate 5-HT1A postsynaptic activation upon chronic dosing, and therefore enhanced analgesia that builds upon the commencement of chronic administration for several weeks. Hence, some tolerance would likely develop with enough time, though probably nowhere near as much as that seen with the opiates.

Personally, I've noticed a significant reduction in my pain threshold caused by my monoamine oxidase inhibitor (MAOI) antidepressant/anxiolytic phenelzine (Nardil), likely induced in part by 5-HT1A postsynaptic receptor activation via the elevations of extracellular serotonin levels it evokes, as well as by increased concentrations of dopamine, and norepinephrine, which probably account for the rest of the effect. In the past, I've read that the MAOIs are capable of causing analgesia on par with or greater than that of codeine.

Not to mention there's also tramadol, which is a combined mu-opioid receptor agonist, NMDA receptor antagonist, 5-HT2C receptor antagonist, norepinephrine reuptake inhibitor, and serotonin releasing agent, the latter property possibly largely explaining its high potency despite only weak opioid effects.

I find these studies to be highly intriguing, and I believe we may very well see a new class of non-addictive (unlike the opiates, on account of the euphoria and pleasure they induce), non-dangerous (as a result of not inducing respiratory depression, again unlike the opioids), high efficacy and selective 5-HT1A receptor full agonists arrive on the market as novel and profound analgesics with few to no side effects in the coming decade or so.

[Smyth]

http://www.ncbi.nlm.nih.gov/pubmed/16921393

Btw, for the actual chemists of the forum, the structure of F13714 is reported as:

(3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone)

I copy&pasted it into chemdraw the other day but it wouldnt recognize that name.

I think it uses english language since the US say 1-butanol, whereas in the UK its butan-1-ol.

[dread]

I think it's like this



fixd

[nuke]

Why not use 8-OH-DPAT? It's not like it's expensive.

I've been really waiting on those crazy illicit chemical suppliers to jump on this one, but no one has.

[negrogesic]

Initial hyperalgesia? That doesnt sound fun...

[rocknroll714]

Originally Posted by negrogesic

Initial hyperalgesia? That doesnt sound fun...

...The infusion of increasing (0.04-0.63 mg/rat/day) doses of F 13640 over a 5-week period induced a large analgesia preceded by a hyperalgesic effect that was small and comparable to that induced by initial exposure to a low, 0.04 mg/rat/day dose...

...The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia...

So, in other words, it can't be too bad. Not to mention, I'd imagine that if a high enough dose was used which significantly activated postsynaptic receptors as well as autoreceptors to the point that the autoreceptor-mediated inhibition of serotonin release were overcome, the initial hyperalgesia would likely be fully bypassed by immediate hypoanalgesia.

[Hammilton]

How high of a dose is that of F 13640? Does anyone know if these are recreational at all at these doses? I doubt it, but this is still super interesting.

[rocknroll714]

Originally Posted by Hammilton

How high of a dose is that of F 13640? Does anyone know if these are recreational at all at these doses? I doubt it, but this is still super interesting.

I'm not sure. And possibly.. I mean highly efficant and selective 5-HT1A receptor full agonists appear to be very powerful anxiolytics and antidepressants. Notably, they enhance dopamine release in certain areas like the ventral tegmental area (a pleasure center of course!), which may mediate some of their therapeutic benefits. For all we know, in high doses they may even cause some euphoria. Even if they don't induce pleasure though I wouldn't mind having one in my system anyway.