Occupational therapy and cooking: A scoping review and future directions.

BACKGROUND: Occupational therapy (OT) has historically used cooking as an intervention and assessment approach across settings. Current practices in OT and the emergence of the multidisciplinary field of culinary medicine highlight the relationship between cooking and health. AIMS/OBJECTIVES: To map the current literature on OT and cooking and to identify key factors that may facilitate collaboration within culinary medicine. MATERIALS AND METHODS: We conducted a scoping review using the Joanna Briggs Institute methodology to identify primary contexts and clinical settings. Publications were analysed using framework thematic analysis to identify OT themes and roles. RESULTS: A total of 56 studies met the criteria for inclusion. The majority of studies (n = 29, 53%) represented home/community settings and brain injury was the largest clinical group (n = 15, 27%). Primary themes related to person (n = 47, 43%), occupation (n = 30 (28%), environment (n = 19, 17%), and psychosocial wellbeing (n = 13, 12%). The primary OT role identified was that of interventionist (n = 48, 86%). CONCLUSIONS/SIGNIFICANCE: OT's holistic practice places cooking within a larger context that can help identify and overcome the barriers to participation. Findings support multiple pathways in which OT can contribute to cooking initiatives for health promotion and potentially expand OT practice in population health.

[Alpha-blockers or phytotherapy as first-line treatment of LUTS/BPH in general medicine: The PERSAT non-interventional study]. / Alpha-bloquants ou phytothérapie en traitement de première intention des SBAU/HBP en médecine générale : l'étude non interventionnelle PERSAT.

PURPOSE: The objective of the PERSAT study was to evaluate first-line treatment of BPH-associated LUTS in real-life conditions. METHODS: This prospective observational study was conducted in France by general practitioners (GP) on patients with moderate to severe LUTS (IPSS ≥12). GPs freely decided to prescribe either an alpha-blocker (AB) or phytotherapeutic treatment (PT). The main criterion was the percentage of responding patients (decrease in total IPSS score ≥3) at 6 months. RESULTS: Of the 849 patients included, 759 were analysed (381 treated with AB and 378 with PT); 718 were followed up at 6 months, 90% of which had no treatment modification. Their inclusion characteristics were similar between the AB and PT groups (mean IPSS: 18.6±4.5 and 17.8±4.1, respectively). Treatment response rates at 6 months were 94.2% [91.2%; 96.4%] in AB and 92.5% [89.2%; 95.1%] in PT. The IPSS decreased by 10.0±5.6 points, with no difference between groups. The proportion of patients bothered by their LUTS (IPSS-QoL ≥4) evolved from 88.5% to 6.5% at 6 months. The improvement of LUTS was perceived by more than 94% of patients (PGI-I) and doctors (CGI-I), 93% of patients were satisfied with the treatment at 6 months, regardless of the treatment initiated. The most reported adverse reactions were ejaculation disorder (3.9% for AB and 0.9% for PT). CONCLUSION: PERSAT confirms in current practice the effectiveness of AB and PT treatments, recommended as first-line treatment in LUTS/BPH. LEVEL OF PROOF: 3.

NLX-112, a highly selective 5-HT1A receptor agonist, mediates analgesia and antidepressant-like activity in rats via spinal cord and prefrontal cortex 5-HT1A receptors, respectively.

NLX-112 (a.k.a. F13640 or befiradol) possesses marked activity in a variety of animal models of pain and of neuropsychiatric disorders; it exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine1A (5-HT1A) receptors. Although NLX-112 has been shown to activate 5-HT1A postsynaptic heteroreceptors in the prefrontal cortex (PFC), a brain region involved in the control of depressive states, the influence of NLX-112 on spinal cord 5-HT1A receptors (implicated in the control of pain) has not been described. Here we report on the ability, in rats, of NLX-112 to elicit analgesia in the intraplantar formalin model of nociceptive pain following intrathecal (i.t.) administration, and its ability to produce antidepressant-like activity in the forced swim test (FST) following in situ PFC microinjection. NLX-112, injected i.t. (L5-L6 region) induced analgesic effects in the formalin model of tonic nociceptive pain. At 20 µg, it almost abolished the effect of formalin on both the paw licking and paw elevation measures, and in both the early (0-5 min after formalin administration, reflecting acute pain) and the late (22.5-27.5 min, reflecting inflammatory pain) phases. The effects of NLX-112 (20 µg i.t.) were reversed by co-administration of 20 µg i.t. of the 5-HT1A receptor antagonist, WAY100635. Furthermore, the analgesic effects of systemically administered NLX-112 (0.63 mg/kg i.p.) were reversed by i.t. administration of WAY100635 (20 µg), most notably on paw licking. Finally, microinjection of NLX-112, bilaterally in the PFC, dose-dependently (MED 4 µg) and markedly reduced immobility in the FST (circa 90% reduction at 32 µg). In conclusion, the present data demonstrate that activation of spinal cord-located 5-HT1A receptors is sufficient for NLX-112 to mediate its analgesic effects in a rat model of tonic nociceptive pain. The data also highlight the involvement of PFC 5-HT1A receptors in the antidepressant-like activity of NLX-112 in the FST. Overall, the study suggests that highly selective and high efficacy 5-HT1A receptors agonists, such as NLX-112, could be useful to treat painful conditions associated with depressive states, through activation of different sub-populations of 5-HT1A receptors.

NLX-112, a highly selective 5-HT1A receptor agonist: Effects on body temperature and plasma corticosterone levels in rats.

NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT1A receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT1A receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT1A receptor agonists in humans. NLX-112 elicited dose-dependent hypothermia (minimal effective dose, MED: 0.31mg/kg p.o.) and also increased plasma corticosterone both by oral and intraperitoneal routes (MED: 0.63mg/kg in both cases). The increase in corticosterone induced by NLX-112 (0.63mg/kg p.o.) was abolished by co-administration of the selective 5-HT1A receptor antagonist, WAY100635. Additionally, NLX-112 also dose-dependently induced flat body posture, forepaw treading and lower lip retraction (MEDs 0.31-0.63mg/kg p.o.). The doses of NLX-112 which induce hypothermia or corticosterone release were similar to those inducing serotonergic behaviors but greater than those reported previously in models of therapeutic-like activity (range 0.04 to 0.16mg/kg). Overall, the present study provides information for clinical dose estimations of NLX-112 and suggests that therapeutic effects may occur at doses below those at which biomarker responses are observed.

NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.

L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16 mg/kg, i.p.) did not impair the ability of L-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.

Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety.

Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects.

Medial arch supports do not significantly alter the knee adduction moment in people with knee osteoarthritis.

OBJECTIVE: This study aimed to evaluate the immediate effects of medial arch supports on indices of medial knee joint load (the peak external knee adduction moment (KAM) and knee adduction angular (KAA) impulse) and knee pain during walking in people with medial knee osteoarthritis (OA). DESIGN: Twenty-one people with medial compartment OA underwent gait analysis in standardised athletic shoes wearing (1) no medial arch supports and (2) prefabricated medial arch supports, in random order. Outcomes were the first and second peaks in the external KAM, the KAA impulse and severity of knee pain during testing. Outcomes were compared across conditions using paired t tests (gait data) and Wilcoxon Signed Ranks test (pain data). RESULTS: There were no significant changes in either first or second peak KAM, or in the KAA impulse, with the addition of medial arch supports (all P > 0.05). Considerable individual variation in response to the arch supports was observed across participants. There was no immediate change in knee pain during walking when medial arch supports were worn (P = 0.56). CONCLUSIONS: This study showed no mean change in any of the measured indices of medial knee load with medial arch supports. No immediate changes in knee pain were evident.

Comparison of milnacipran, duloxetine and pregabalin in the formalin pain test and in a model of stress-induced ultrasonic vocalizations in rats.

Milnacipran and duloxetine, serotonin/noradrenalin reuptake inhibitors, and pregabalin, a alpha(2)-delta(1) Ca(2+) channel blocker, are efficacious against fibromyalgia, a condition characterized by diffuse chronic pain and associated with stress. We compared these compounds (i.p. route), in rat models of acute/inflammatory pain (2.5% intraplantar formalin) and stress-induced ultrasonic vocalization (USV: 22kHz calls following presentation of a conditioned stimulus previously associated with foot-shocks). In the formalin test, milnacipran dose-dependently attenuated paw elevation and licking (minimal effective dose, MED: 2.5mg/kg for licking/late phase). Duloxetine was slightly more potent (MED=0.63). Pregabalin also reduced paw licking/late phase (MED=0.63), but was inactive up to 160mg/kg for paw elevation (both phases) and paw licking (early phase). Milnacipran dose-dependently reduced USV (MED=10, near total inhibition at 20mg/kg); duloxetine was less potent (MED=20). Pregabalin (2.5-80mg/kg) was only significantly active at 40mg/kg. Milnacipran, duloxetine and pregabalin possess analgesic activity in the formalin test on paw licking/late phase (corresponding to inflammatory pain with a central sensitization component). In the stress-induced USV model, milnacipran was the most potent and efficacious compound. To summarize, reduction of formalin-induced paw licking/late phase might constitute a useful indicator of potential activity against inflammatory/centrally sensitized pain, as might be expressed in fibromyalgia.

Chronic restraint stress induces mechanical and cold allodynia, and enhances inflammatory pain in rat: Relevance to human stress-associated painful pathologies.

Whereas acute stress often results in analgesia, chronic stress can trigger hyperalgesia/allodynia. This influence of long-term stress on nociception is relevant to numerous painful pathologies, such as fibromyalgia (FM), characterized by diffuse muscular pain (hyperalgesia) and/or tenderness (allodynia). Hence, there is a need for pre-clinical models integrating a chronic-stress dimension to the study of pain. Here, we assessed the effects of protracted/intermittent stress produced by daily, 1h restraint periods in cylinders, 4 days/week over 5 weeks, on eight models of hyperalgesia and allodynia in rats. This type of stress potentiated chemical hyperalgesia in the formalin model (160 and 76% increase of pain score above controls, during the early and late phases, respectively). It also produced thermal allodynia in response to cold (paw acetone test: 200% increase of allodynia score during week 3-5) and heat (42 degrees C tail immersion test: 15% decrease of withdrawal threshold, from week 2 onward). This stress also resulted in mechanical allodynia in the von Frey filaments model (60% decrease in threshold during week 2-5). However, such a stress regimen had no influence in the Randall-Selitto test of mechanical hyperalgesia, and in the tail immersion models of cold (4 degrees C) or hot (48 degrees C) thermal hyperalgesia, as well as cold (15 degrees C) allodynia. This model of prolonged/intermittent restraint stress may be useful in investigating the mechanisms linking stress and pain, and provide an assay to assess the potential therapeutic efficacy of drugs targeted against painful pathologies with a strong stress component, including but not restricted to FM.

5-HT1A receptors are involved in the effects of xaliproden on G-protein activation, neurotransmitter release and nociception.

BACKGROUND AND PURPOSE: Xaliproden (SR57746A) is a 5-HT(1A) receptor agonist and neurotrophic agent that reduces oxaliplatin-mediated neuropathy in clinical trials. The present study investigated its profile on in vitro transduction, neurochemical responses and acute nociceptive pain tests in rats. EXPERIMENTAL APPROACH: Xaliproden was tested on models associated with 5-HT(1A) receptor activation including G-protein activation, extracellular dopamine and 5-HT levels measured by microdialysis and formalin-induced pain. Activation of 5-HT(1A) receptors was confirmed by antagonism with WAY100635. KEY RESULTS: Xaliproden exhibited high affinity for rat (r) and human (h) 5-HT(1A) receptors (pK(i)= 8.84 and 9.00). In [(35)S]GTPgammaS (guanosine 5'-O-(3-[(35)S]thio)triphosphate) assays it activated both hippocampal r5-HT(1A)[pEC(50)/E(MAX) of 7.58/61% (%5-HT)] and recombinant h5-HT(1A) receptors (glioma C6-h5-HT(1A): 7.39/62%; HeLa-h5-HT(1A): 7.24/93%). In functional [(35)S]GTPgammaS autoradiography, xaliproden induced labelling in structures enriched with 5-HT(1A) receptors (hippocampus, lateral septum, prefrontal and entorhinal cortices). Xaliproden inhibited in vivo binding of [(3)H]WAY100635 to 5-HT(1A) receptors in mouse frontal cortex and hippocampus (ID(50): 3.5 and 3.3 mg x kg(-1), p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5-HT levels (ED(50): 1.2 and 0.7 mg x kg(-1), i.p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED(50): 1 and 3 mg x kg(-1), i.p. respectively) following formalin injection in the paw. All effects were reversed by pretreatment with WAY100635. CONCLUSIONS AND IMPLICATIONS: These results indicate that activation of 5-HT(1A) receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5-HT(1A) receptor activation as an anti-nociceptive strategy.

F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. III. Activity in models of cognition and negative symptoms.

BACKGROUND AND PURPOSE: The D(2)/D(3) receptor antagonist, D(4) receptor partial agonist, and high efficacy 5-HT(1A) receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the 'serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia. EXPERIMENTAL APPROACH: F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems. KEY RESULTS: Through 5-HT(1A) activation, F15063 partially alleviated (MED: 0.04 mg kg(-1)) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg(-1), F15063 reduced interaction by itself. F15063 (0.16 mg kg(-1)) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04-0.63 mg kg(-1)) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D(4) partial agonism, as it was blocked by the D(4) antagonist L745,870. Finally, F15063 up to 40 mg kg(-1) did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating. CONCLUSIONS AND IMPLICATIONS: The balance of D(2)/D(3), D(4) and 5-HT(1A) receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.

F15063, a compound with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. II. Activity in models of positive symptoms of schizophrenia.

BACKGROUND AND PURPOSE: F15063 is a high affinity D(2)/D(3) antagonist, D(4) partial agonist, and high efficacy 5-HT(1A) agonist, with little affinity (40-fold lower than for D(2) receptors) at other central targets. Here, the profile of F15063 was evaluated in models of positive symptoms of schizophrenia and motor side-effects. EXPERIMENTAL APPROACH: Rodent behavioural tests were based on reversal of hyperactivity induced by psychostimulants and on measures of induction of catalepsy and 'serotonin syndrome'. KEY RESULTS: F15063 potently (ED(50)s: 0.23 to 1.10 mg kg(-1) i.p.) reversed methylphenidate-induced stereotyped behaviors, blocked d-amphetamine and ketamine hyperlocomotion, attenuated apomorphine-induced prepulse inhibition (PPI) deficits, and was active in the conditioned avoidance test. In mice, it reversed apomorphine-induced climbing (ED(50)=0.30 mg kg(-1) i.p.). F15063, owing to its 5-HT(1A) agonism, did not produce (ED(50)>40 mg kg(-1) i.p.) catalepsy in rats and mice, a behavior predictive of occurrence of extra-pyramidal syndrome (EPS) in man. This absence of cataleptogenic activity was maintained upon sub-chronic treatment of rats for 5 days at 40 mg kg(-1) p.o. Furthermore, F15063 did not induce the 'serotonin syndrome' in rats (flat body posture and forepaw treading: ED(50) >32 mg kg(-1) i.p.). CONCLUSIONS AND IMPLICATIONS: F15063 conformed to the profile of an atypical antipsychotic, with potent actions in models of hyperdopaminergic activity but without inducing catalepsy. These data suggest that F15063 may display potent antipsychotic actions with low EPS liability. This profile is complemented by a favourable profile in rodent models of negative symptoms and cognitive deficits of schizophrenia (companion paper).

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.

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 receptor subtypes involved in the spinal antinociceptive effect of acetaminophen in rats.

The present study was designed to investigate which subtype of spinal 5-HT receptors were involved in acetaminophen-induced antinociception using the paw-pressure test. Propacetamol (prodrug of acetaminophen, 400 mg/kg, injected intravenously, corresponding to 200 mg/kg of acetaminophen) produced a significant antinociceptive effect in this test. This effect was at least partially inhibited by intrathecal (i.t.) pretreatment with the 5-HT(1B) (penbutolol), 5-HT(2A) (ketanserin), 5-HT(2C) (mesulergine) receptor antagonists, but not by the 5-HT(1A) (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride, WAY 100635) and 5-HT(3) (granisetron) receptor antagonists. This profile was very close to that obtained recently with 5-HT, which suggests an implication of 5-HT in the spinal antinociceptive effect of acetaminophen. These results, the lack of binding of acetaminophen to 5-HT receptors and the increase of central 5-HT levels induced by this drug suggest that acetaminophen-induced antinociception could be indirectly mediated by 5-HT.

In the formalin model of tonic nociceptive pain, 8-OH-DPAT produces 5-HT1A receptor-mediated, behaviorally specific analgesia.

The experiments examined antinociceptive and intrinsic behavioral effects induced by the prototypical 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino] tetralin) in rats. 8-OH-DPAT (0.01-2.5 mg/kg, subcutaneous (s.c.)) reduced both the paw licking and paw elevation induced by (2.5%) formalin injection into the plantar surface of the right hindpaw; it also produced forepaw treading. All of these effects were completely blocked by pretreatment with WAY 100635 (N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride) (0.16 mg/kg, s.c.); prazosin (0.63 mg/kg, s.c.) inhibited forepaw treading, but not 8-OH-DPAT's action on paw elevation and paw licking. Repeated injection of 8-OH-DPAT (0.63 mg/kg, s.c.) twice daily for 4 days, markedly reduced 8-OH-DPAT's ability to produce forepaw treading, but exerted only little and inconsistent effects on its paw licking and paw elevation-inhibiting action. The data indicate that 8-OH-DPAT exerts an analgesic action in the formalin model of tonic nociceptive pain; this action is mediated by 5-HT(1A) receptors, and is not confounded by the productive sign (i.e., forepaw treading) of the 5-HT syndrome which 8-OH-DPAT also induces.

Effect of intrathecal administration of serotonin in chronic pain models in rats.

The present study examined the effects of intrathecal (i.t.) administration of 5-hydroxytryptamine (5-HT; 0.1-100 microg) on mechanical hyperalgesia associated with neuropathic pain (chronic constriction of the sciatic nerve model and diabetic model) and inflammatory pain (carrageenan and polyarthritic models) in rats. Results demonstrated that the hyperalgesia observed in the mononeuropathic and diabetic rats was attenuated by 5-HT; the active dose, however, was 100- to 1000-fold higher than that required in normal rats, and was moderately effective. In the two experimental models of inflammatory pain, 5-HT was not markedly or similarly active. In the carrageenan model, 5-HT at the highest dose was only weakly effective whereas in the polyarthritic model it was inactive. Together, these results show that 5-HT has antinociceptive effects in several rat pain models, except in the model of diffuse pain (polyarthritic rats). Its antinociceptive effects in these models, however, are slight and differ from those observed in normal rats.

Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats.

The present study was designed to investigate which subtypes of spinal 5-HT receptors are involved in 5-HT-induced antinociception using the mechanical pain test. Serotonin and various selective antagonists or agonists for 5-HT receptor subtypes (5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2C), 5-HT(3) and 5-HT(4)) were administered intrathecally (i.t.) in rats. The i.t. injection of 5-HT (1 microg) produced significant antinociceptive effects using the paw pressure test. Pretreatment with the 5-HT(2C) receptor antagonist mesulergine (1 and 10 microg) and the 5-HT(3) receptor antagonist tropisetron (1 and 10 microg) reversed totally the antinociception induced by 5-HT. Furthermore, at a dose of 10 microg, both the 5-HT(2A) receptor antagonist ketanserin and the 5-HT(1B) receptor antagonist penbutolol, but neither the 5-HT(1A) receptor antagonist WAY 100635 nor the 5-HT(4) receptor antagonist GR113808, attenuated the antinociceptive effect induced by 5-HT. In addition, an i.t. injection of the 5-HT(3) agonist mCPBG induced significant antinociceptive effects whereas the 5-HT(2) agonist DOI did not produce analgesia. These results suggest that although the precise degree of the involvement of spinal serotonergic 5-HT(3) receptors remains to be elucidated due to some differences in the effect of agonists or antagonists, these receptors seem to play a role in the antinociceptive effect of 5-HT against a mechanical acute noxious stimulus. The involvement of 5-HT(2C) is more questionable due to the observed discrepancies between the effects of the used agonist and antagonist. 5-HT(1A) and 5-HT(4) receptors do not seem to be involved. In addition, a possible functional interaction between spinal serotonergic receptors may exist.

The role of formalin-induced pain in morphine tolerance, withdrawal, and reward.

The effect of a commonly used experimental pain-induction procedure (formalin injection into a hindpaw site) on morphine tolerance, withdrawal, and reward was examined in rats. Results suggest that the effects of morphine are different in the organism that is experiencing pain at the time it receives the drug than in the organism that is pain free. The presence of pain at the time of each morphine administration decreased analgesic tolerance, decreased naloxone-precipitated withdrawal, and enhanced the rewarding effect of the opiate. These findings, together with those of previous studies, suggest that theories of opiate tolerance, withdrawal, and reward should incorporate the effects of pain.