Abimael González-Hernández

Oxytocin and analgesia: future trends.

Although best known for its function in lactation, uterine contraction during parturition, and for its role in social behaviour, the neurohormone oxytocin (OT) has also been implicated as an important mediator in endogenous analgesia. Electrophysiological experiments show that OT is able to block the activity of nociceptive Aδ- and C-fibres without affecting non-nociceptive fibres (Aβ-fibres) [1,2]. Indeed, OT could exert its antinociceptive effects at spinal [3–5], supraspinal [6], and at peripheral levels [3,7,8] (Figure 1).

Peripheral oxytocin receptors inhibit the nociceptive input signal to spinal dorsal horn wide-dynamic-range neurons

Abstract Oxytocin (OT) has emerged as a mediator of endogenous analgesia in behavioral and electrophysiological experiments. In fact, OT receptors (OTRs) in the spinal dorsal horn participate in a selective inhibition of the neuronal activity mediated by A&dgr; and C fibers but not A&bgr; fibers. This study shows that OTRs are expressed in the terminal nerve endings and are able to inhibit nociceptive neuronal firing. Indeed, local peripheral OT blocked the first sensorial activity of A&dgr; and C fibers recorded in the spinal cord neurons. Furthermore, using the formalin behavioral nociceptive test, we demonstrated that only ipsilateral OTR activation inhibits pain behavior. Our data are reinforced by the fact that the OTR protein is expressed in the sciatic nerve. Consistent with this, immunofluorescence of primary afferent fibers suggest that OTRs could be located in nociceptive-specific terminals of the skin. Taken together, our results suggest that OTRs could be found in nociceptive terminals and that on activation they are able to inhibit nociceptive input.

Successful Pain Management with Epidural Oxytocin.

Pain is a prevalent symptom experienced by more than 70% of patients with advanced cancer. Although opioid analgesics are recognized as the first-line treatment in moderate to severe cancer pain, patients can develop intolerable adverse effects (e.g., respiratory depression). In this context, the discovery of new compounds to treat pain remains as a key challenge. Recently, oxytocin has emerged as an interesting molecule to induce analgesia [1–4]. Basic research in rodents shows that spinal oxytocin (endogenous or exogenous) induces antinociception [5,6]. Therefore, although a recent Phase I study showed that intrathecal oxytocin failed to modify the pain score to noxious stimuli [3], the potential analgesic effect of this peptide in hypersensitivity states remains unclear. Here, we report two cases of intense chronic pain and its responses to epidural oxytocin-based treatment. Both cases were reviewed and approved by our institutional ethic committee following the ethical standards established in the Declaration of Helsinki and the patients gave their informed consent.

Hypothalamic paraventricular nucleus stimulation enhances c-Fos expression in spinal and supraspinal structures related to pain modulation

The hypothalamic paraventricular nuclei (PVN) inhibits spinal nociception. Furthermore, projections from the PVN to other structures related to pain modulation exist, but a functional interaction has not yet been fully demonstrated. As an initial approach, we show here that PVN electric stimulation with the same parameters used to induce analgesia in rats enhances c-Fos expression not only in the dorsal horn of the spinal cord but also in the nucleus raphe magnus, locus coeruleus and the periaqueductal gray area. These results suggest that a functional interaction between these structures could occur, possibly to assure a mechanism of endogenous analgesia.

Side effects associated with current and prospective antimigraine pharmacotherapies

ABSTRACT Introduction: Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT1B/1D, 5-HT1F and CGRP receptors but, unfortunately, they induce some cardiovascular and central side effects that lead to poor treatment adherence/compliance. Therefore, new antimigraine drugs are being explored. Areas covered: This review considers the adverse (or potential) side effects produced by current and prospective antimigraine drugs, including medication overuse headache (MOH) produced by ergots and triptans, the side effects observed in clinical trials for the new gepants and CGRP antibodies, and a section discussing the potential effects resulting from disruption of the cardiovascular CGRPergic neurotransmission. Expert opinion: The last decades have witnessed remarkable developments in antimigraine therapy, which includes acute (e.g. triptans) and prophylactic (e.g. β-adrenoceptor blockers) antimigraine drugs. Indeed, the triptans represent a considerable advance, but their side effects (including nausea, dizziness and coronary vasoconstriction) preclude some patients from using triptans. This has led to the development of the ditans (5-HT1F receptor agonists), the gepants (CGRP receptor antagonists) and the monoclonal antibodies against CGRP or its receptor. The latter drugs represent a new hope in the antimigraine armamentarium, but as CGRP plays a role in cardiovascular homeostasis, the potential for adverse cardiovascular side effects remains latent.

The potential role of serotonergic mechanisms in the spinal oxytocin-induced antinociception

The role of oxytocin (OXT) in pain modulation has been suggested. Indeed, hypothalamic paraventricular nuclei (PVN) electrical stimuli reduce the nociceptive neuronal activity (i.e., neuronal discharge associated with activation of Aδ- and C-fibers) of the spinal dorsal horn wide dynamic range (WDR) cells and nociceptive behavior. Furthermore, raphe magnus nuclei lesion reduces the PVN-induced antinociception, suggesting a functional interaction between the OXT and the serotoninergic system. The present study investigated in Wistar rats the potential role of spinal serotonergic mechanisms in the OXT- and PVN-induced antinociception. In long-term secondary mechanical allodynia and hyperalgesia induced by formalin or extracellular unitary recordings of the WDR cells we evaluated the role of 5-hydroxytryptamine (5-HT) effect on the OXT-induced antinociception. All drugs were given intrathecally (i.t.). OXT (1×10-5-1×10-4nmol) or 5-HT (1×10-3-1×10-1nmol) prevented the formalin-induced sensitization, an effect mimicked by PVN stimulation. Moreover, administration of OXT (1×10-5nmol) plus 5-HT (1×10-3nmol) at ineffective doses, produced antinociception. This effect was antagonized by: (i) d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH29]OVT (oxytocin receptor antagonist; 2×10-2nmol); or (ii) methiothepin (a non-specific 5-HT1/2/5/6/7 receptor antagonist; 80nmol). Similar results were obtained with PVN stimulation plus 5-HT (5×10-5nmol). In WDR cell recordings, the PVN-induced antinociception was enhanced by i.t. 5-HT and partly blocked when the spinal cord was pre-treated with methiothepin (80nmol). Taken together, these results suggest that serotonergic mechanisms at the spinal cord level are partly involved in the OXT-induced antinociception.

Spinal LTP induced by sciatic nerve electrical stimulation enhances posterior triangular thalamic nociceptive responses

Long-term potentiation (LTP) can be induced by electrical stimulation and gives rise to an increase in synaptic strength at the first relay. This phenomenon has been associated with learning and memory and also could be the origin of several pathological states elicited by an initial strong painful stimulus, such as some forms of neuropathic pain. We used high-frequency electrical stimulation of the sciatic nerve in anesthetized rats to produce spinal LTP. To evaluate the effect of spinal LTP on the activity of neurons in the posterior triangular nucleus of the thalamus (PoT), we applied an electrical stimulation (40 stimuli; 1ms; 0.5Hz; 1.5mA) to cutaneous tissues at 10-min intervals during at least 3h. In the majority of cases, PoT cells did not respond to cutaneous stimulation before LTP, but 50min after LTP induction PoT cells progressively began responding to the cutaneous stimulation. Furthermore, after 3h of LTP induction, PoT neurons could respond to cutaneous stimulation applied to different paws. Interestingly, the conduction velocities for the receptive field responses from the paw to the PoT cells were compatible with those of Aδ-fibers. Since PoT cells project to the insular cortex, the progressive increase in PoT activity and also the progressive unmasking of somatic receptive fields in response to LTP, place these cells in a key position to detect pain stimuli following central sensitization.

Oxytocin inhibits the rat medullary dorsal horn Sp5c/C1 nociceptive transmission through OT but not V 1A receptors

ABSTRACT The medullary dorsal horn (MDH or Sp5c/C1 region) plays a key role modulating the nociceptive input arriving from craniofacial structures. Some reports suggest that oxytocin could play a role modulating the nociceptive input at the MDH level, but no study has properly tested this hypothesis. Using an electrophysiological and pharmacological approach, the present study aimed to determine the effect of oxytocin on the nociceptive signaling in the MDH and the receptor involved. In sevoflurane, anesthetized rats, we performed electrophysiological unitary recordings of second order neurons at the MDH region responding to peripheral nociceptive‐evoked responses of the first branch (V1; ophthalmic) of the trigeminal nerve. Under this condition, we constructed dose‐response curves analyzing the effect of local spinal oxytocin (0.2–20 nmol) on MDH nociceptive neuronal firing. Furthermore, we tested the role of oxytocin receptors (OTR) or vasopressin V1A receptors (V1AR) involved in the oxytocin effects. Oxytocin dose‐dependently inhibits the peripheral‐evoked activity in nociceptive MDH neurotransmission. This inhibition is associated with a blockade of neuronal activity of A&dgr;‐ and C‐fibers. Since this antinociception was abolished by pretreatment (in the MDH) with the potent and selective OTR antagonist (L‐368,899; 20 nmol) and remained unaffected after the V1AR antagonist (SR49059; 20 nmol or 200 nmol), the role of OTR is implied. This electrophysiological study demonstrates that oxytocin inhibits the peripheral‐evoked neuronal activity at MDH, through OTR activation. Thus, OTR may represent a new potential drug target to treat craniofacial nociceptive dysfunction in the MDH. HIGHLIGHTSMedullary dorsal horn (MDH) is involved in craniofacial nociception.Oxytocin administration at MDH inhibits the peripheral‐evoked nociception.Blockade of oxytocin receptors (OTR) inhibits the oxytocin‐induced antinociception.The effect of oxytocin on MDH neurotransmission is not mediated by V1A receptors.Relevance of oxytocinergic neurotransmission at spinal trigeminal level is suggested.

The role of peripheral vasopressin 1A and oxytocin receptors on the subcutaneous vasopressin antinociceptive effects

Vasopressin (AVP) seems to play a role as an antinociceptive neurohormone, but little is known about the peripheral site of action of its antinociceptive effects. Moreover, AVP can produce motor impairment that could be confused with behavioural antinociception. Finally, it is not clear which receptor is involved in the peripheral antinociceptive AVP effects.

Response to Letter to the Editor by Eisenach and Yaksh on “Successful Pain Management with Epidural Oxytocin”

Response to Ethical concerns regarding human study, We are grateful to Eisenach and Yaksh for their interest on our work [1]. Regarding their letter published in this issue [2], we have well noted their feedback and have some concerns with their comments. First, we are in agreement in the awareness that in humans exposed to a novel or experimental treatment, researchers need to carefully attend the international and local ethic guidelines and rules of experimentation. For us, this is the case (we have the approval of our IRB, and we have the informed consent of the patients) and we are following those guidelines to continue with our scientific work. In addition, we (and all Editorials Boards) need to understand that in each case, the guidelines also should take into account all the circumstances in which a new treatment could improve a pathological state. Indeed, as stated by Elger and Hoppe [3], “the treatment does not follow a study protocol and if the patient provided informed consent, the physician is not only allowed, but obligated to apply approved (labeled and off-labeled) therapy.” In addition, we followed the four principles of Beauchamp and Childress, which indicate that patient–practitioner relationship should be guided by (1) autonomy, (2) beneficence, (3) nonmaleficence, and (4) justice [4]. Second, as you noticed in our report, although the patients had an adequate level of analgesia with the morphine plus ropivacaine regime, their quality of life was poor, and consequently, it is necessary to keep in mind that analgesia is not the unique factor when quality of life is evaluated. With the standard treatment (morphine plus ropivacaine), our patients presented a poor state of alertness and interaction with their relatives; in addition, the patients started to present serious side effects such as respiratory depression. In this context, it is important to point out that oxytocin was administered to cancer patients in their terminal state, with a short life expectancy. Significantly, epidural administration of oxytocin plus ropivacaine gave our patients the same level of analgesia and additionally a better level of consciousness that allowed them to interact in a normal way with their relatives. We think that offering such outcome to a terminal patient is not only ethical but a priority.